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Health sector has spent $464 million on lobbying in 2020
, according to the Center for Responsive Politics.
PhRMA spent $20.7 million on lobbying through the end of September, good enough for third on the overall list of U.S. companies and organizations. Three other members of the health sector made the top 10: the American Hospital Association ($18.3 million), BlueCross/BlueShield ($16.3 million), and the American Medical Association ($15.2 million), the center reported.
Total spending by the health sector was $464 million from Jan. 1 to Sept. 30, topping the finance/insurance/real estate sector at $403 million, and miscellaneous business at $371 million. Miscellaneous business is the home of the U.S. Chamber of Commerce, the annual leader in such spending for the last 20 years, based on data from the Senate Office of Public Records.
The largest share of health sector spending came from pharmaceuticals/health products, with a total of almost $233 million, just slightly more than the sector’s four other constituents combined: hospitals/nursing homes ($80 million), health services/HMOs ($75 million), health professionals ($67 million), and miscellaneous health ($9.5 million), the center said on OpenSecrets.org.
Taking one step down from the sector level, that $233 million made pharmaceuticals/health products the highest spending of about 100 industries in 2020, nearly doubling the efforts of electronics manufacturing and equipment ($118 million), which came a distant second. Hospitals/nursing homes was eighth on the industry list, the center noted.
, according to the Center for Responsive Politics.
PhRMA spent $20.7 million on lobbying through the end of September, good enough for third on the overall list of U.S. companies and organizations. Three other members of the health sector made the top 10: the American Hospital Association ($18.3 million), BlueCross/BlueShield ($16.3 million), and the American Medical Association ($15.2 million), the center reported.
Total spending by the health sector was $464 million from Jan. 1 to Sept. 30, topping the finance/insurance/real estate sector at $403 million, and miscellaneous business at $371 million. Miscellaneous business is the home of the U.S. Chamber of Commerce, the annual leader in such spending for the last 20 years, based on data from the Senate Office of Public Records.
The largest share of health sector spending came from pharmaceuticals/health products, with a total of almost $233 million, just slightly more than the sector’s four other constituents combined: hospitals/nursing homes ($80 million), health services/HMOs ($75 million), health professionals ($67 million), and miscellaneous health ($9.5 million), the center said on OpenSecrets.org.
Taking one step down from the sector level, that $233 million made pharmaceuticals/health products the highest spending of about 100 industries in 2020, nearly doubling the efforts of electronics manufacturing and equipment ($118 million), which came a distant second. Hospitals/nursing homes was eighth on the industry list, the center noted.
, according to the Center for Responsive Politics.
PhRMA spent $20.7 million on lobbying through the end of September, good enough for third on the overall list of U.S. companies and organizations. Three other members of the health sector made the top 10: the American Hospital Association ($18.3 million), BlueCross/BlueShield ($16.3 million), and the American Medical Association ($15.2 million), the center reported.
Total spending by the health sector was $464 million from Jan. 1 to Sept. 30, topping the finance/insurance/real estate sector at $403 million, and miscellaneous business at $371 million. Miscellaneous business is the home of the U.S. Chamber of Commerce, the annual leader in such spending for the last 20 years, based on data from the Senate Office of Public Records.
The largest share of health sector spending came from pharmaceuticals/health products, with a total of almost $233 million, just slightly more than the sector’s four other constituents combined: hospitals/nursing homes ($80 million), health services/HMOs ($75 million), health professionals ($67 million), and miscellaneous health ($9.5 million), the center said on OpenSecrets.org.
Taking one step down from the sector level, that $233 million made pharmaceuticals/health products the highest spending of about 100 industries in 2020, nearly doubling the efforts of electronics manufacturing and equipment ($118 million), which came a distant second. Hospitals/nursing homes was eighth on the industry list, the center noted.
New technologies aim to improve ovarian cancer detection
Encouraging trends abound in the management of ovarian cancer. As rates of ovarian disease continue to decline, there has also been a notable increase in tools for detecting it earlier in its course.
To better understand these developments, this news organization reached out to Rebecca Stone, MD, an ovarian cancer expert and associate professor of gynecologic oncology at Johns Hopkins University, in Baltimore, Maryland. This interview has been edited for length and clarity.
There has been a decline in the rates of ovarian cancer in recent years. What are the possible causes of this?Dr. Stone: The number of new cases in the United States has actually been declining over the past 2 decades. This is thought to be attributable to the increased prescribing of oral contraceptive pills in the late 1990s and the uptake of preventive measures, such as risk-reducing gynecologic surgery for women with genetic predisposition to ovarian cancer, as well as opportunistic salpingectomy in the general population. Opportunistic salpingectomy was introduced about 10 years ago. It is a surgical means for primary prevention of tubo-ovarian cancer by removing both fallopian tubes at the time of elective surgery for women who have completed childbearing or in lieu of “tying the tubes” for women who desire permanent surgical sterility.
What can you tell us about a recent study suggesting that high-grade serous epithelial ovarian cancer may be detected earlier in the course of the disease by testing for TP53 clonal variants in DNA from Papanicolaou (Pap) tests performed during cervical cancer screening?
The idea here is that early mutational events that ultimately result in the development of epithelial ovarian cancer can be detected by performing gene sequencing on genetic material collected at the time of routine Pap smear screening done for cervical cancer. Pap tests are known to contain cells and genetic material shed from the fallopian tubes, where the precancerous lesions thought to give rise to epithelial ovarian cancer, predominantly serous epithelial ovarian cancers, start.
p53 gene mutations are thought to occur early in the evolution of ovarian cancer. There are data indicating that these mutations actually occur in cells lining the fallopian tubes. Polymerase chain reaction–based DNA/gene sequencing performed on cervical fluid collected by Pap smears could detect these p53-mutated cells shed from the fallopian tubes.
A strength of this study is that it included healthy controls. None of their Pap smears screened positive for the p53 mutations, unlike the Pap smears of women predating their diagnosis of ovarian cancer. Limitations of the study include the fact that it had a small sample size. Findings will need to be confirmed in a larger patient population.
Also, the study only looked for p53 gene mutations. Ovarian cancers, like other cancers, are largely thought to occur when there is a buildup of mutations in critical genes that result in uncontrolled cell growth and division. These genetic changes/mutations are acquired during a person’s lifetime. Thus, there are likely early genetic changes/mutations that occur in addition to p53 mutations that ultimately lead to the development of ovarian cancer. Detecting these along with p53 mutations could improve the sensitivity/detection rate of the screening strategy that the authors are investigating.
Finally, this screening strategy may not prove effective for the early detection of all histologic subtypes of epithelial ovarian cancer or for nonepithelial ovarian cancers.
What other recent developments in the diagnosis of ovarian cancer should clinicians be aware of?
Liquid biopsies using circulating tumor DNA (ctDNA) have shown promising results for cancer detection and management, including ovarian cancer. However, further clarification is needed to define the minimum tumor size/burden detectable using ctDNA-based approaches. Moreover, large prospective studies are needed to determine the clinical utility of ctDNA detection for early diagnosis of ovarian cancer and its impact on patient outcomes.
DNA methylation is an early event in carcinogenesis and can be detected in blood plasma samples from cancer patients. Data related to the discovery and validation of discriminated methylated DNA marker candidates extracted from ovarian cancer tissues were presented at the American Society of Clinical Oncology meeting this year. Findings were subsequently evaluated in plasma from women with and without ovarian cancer.
In addition to blood, peritoneal fluid and uterine lavage have been used to obtain cell pellets that are used for the identification of common mutant genes – TP53, BRCA1, and BRCA2. These body fluids have also been shown as the source of tumor-derived material that can be used to differentiate between ovarian cancer patients and healthy individuals.
Further studies are needed to determine the sensitivity and specificity of other noninvasive tests for the diagnosis of ovarian cancer.
The American Cancer Society issued a statement that the human papillomavirus (HPV) test is the preferred cervical cancer screening tool. Why do they prefer the HPV test over the Pap test?
The American Cancer Society recommends that cervical cancer testing (screening) begin at age 25 years. Women aged 25-65 years should have a primary HPV test every 5 years. If primary HPV testing is not available, screening may be done with either a co-test that combines an HPV test with a Pap test every 5 years or a Pap test alone every 3 years.
The HPV test is widely available. The cost of an HPV test is approximately $44 (unit cost, 2014 USD). The cost of a Pap test is approximately $30 (unit cost, 2014 USD).
The HPV test is preferred over cytologic testing (Pap) for several reasons.
Firstly, in well-designed studies, the sensitivity of a single Pap smear for detecting high-grade precancer of the cervix is around 50%, which is less than optimal for a cancer screening test. Sensitivity means the chance that, if you have the disease (in this case, high-grade precancer of the cervix), the test will detect it. In particular, cytology is known to have an even more limited ability to detect glandular precancers, which arise in the endocervical canal rather than on or in close proximity to the exterior surface of the cervix (ectocervix). Thus, HPV-based screening programs hold the promise of improving detection of cervical adenocarcinoma.
Secondly, to function reliably, cytology programs require substantial infrastructure, highly qualified human resources, and a well‐defined quality-control system, which have proved to be costly and difficult to implement. This results in global disparities in cytology-based cervical cancer screening programs.
Thirdly, although co‐testing with both cytology and HPV tests is an option for screening programs, studies have confirmed that there is limited benefit from adding cytology to HPV screening. Long‐term studies from Kaiser Permanente that included over 1 million women found that HPV testing has a very high negative predictive value for precancerous lesions. Women with negative HPV tests were very unlikely to develop precancerous lesions in the following 5 years. The 5‐year risk of high-grade precancer or cancer of the cervix following a negative HPV test was 0.14%, whereas for women with a negative cytology, it was 0.31%. The screening benefit of co‐testing is largely driven by HPV testing and not cytology.
So, in summary, HPV testing is preferred over cytologic screening for cervical cancer, given its improved sensitivity and quality assurance, the opportunity to automate testing, and ultimately, its prospect of reducing the overall number of lifetime screenings for women.
Dr. Stone has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Encouraging trends abound in the management of ovarian cancer. As rates of ovarian disease continue to decline, there has also been a notable increase in tools for detecting it earlier in its course.
To better understand these developments, this news organization reached out to Rebecca Stone, MD, an ovarian cancer expert and associate professor of gynecologic oncology at Johns Hopkins University, in Baltimore, Maryland. This interview has been edited for length and clarity.
There has been a decline in the rates of ovarian cancer in recent years. What are the possible causes of this?Dr. Stone: The number of new cases in the United States has actually been declining over the past 2 decades. This is thought to be attributable to the increased prescribing of oral contraceptive pills in the late 1990s and the uptake of preventive measures, such as risk-reducing gynecologic surgery for women with genetic predisposition to ovarian cancer, as well as opportunistic salpingectomy in the general population. Opportunistic salpingectomy was introduced about 10 years ago. It is a surgical means for primary prevention of tubo-ovarian cancer by removing both fallopian tubes at the time of elective surgery for women who have completed childbearing or in lieu of “tying the tubes” for women who desire permanent surgical sterility.
What can you tell us about a recent study suggesting that high-grade serous epithelial ovarian cancer may be detected earlier in the course of the disease by testing for TP53 clonal variants in DNA from Papanicolaou (Pap) tests performed during cervical cancer screening?
The idea here is that early mutational events that ultimately result in the development of epithelial ovarian cancer can be detected by performing gene sequencing on genetic material collected at the time of routine Pap smear screening done for cervical cancer. Pap tests are known to contain cells and genetic material shed from the fallopian tubes, where the precancerous lesions thought to give rise to epithelial ovarian cancer, predominantly serous epithelial ovarian cancers, start.
p53 gene mutations are thought to occur early in the evolution of ovarian cancer. There are data indicating that these mutations actually occur in cells lining the fallopian tubes. Polymerase chain reaction–based DNA/gene sequencing performed on cervical fluid collected by Pap smears could detect these p53-mutated cells shed from the fallopian tubes.
A strength of this study is that it included healthy controls. None of their Pap smears screened positive for the p53 mutations, unlike the Pap smears of women predating their diagnosis of ovarian cancer. Limitations of the study include the fact that it had a small sample size. Findings will need to be confirmed in a larger patient population.
Also, the study only looked for p53 gene mutations. Ovarian cancers, like other cancers, are largely thought to occur when there is a buildup of mutations in critical genes that result in uncontrolled cell growth and division. These genetic changes/mutations are acquired during a person’s lifetime. Thus, there are likely early genetic changes/mutations that occur in addition to p53 mutations that ultimately lead to the development of ovarian cancer. Detecting these along with p53 mutations could improve the sensitivity/detection rate of the screening strategy that the authors are investigating.
Finally, this screening strategy may not prove effective for the early detection of all histologic subtypes of epithelial ovarian cancer or for nonepithelial ovarian cancers.
What other recent developments in the diagnosis of ovarian cancer should clinicians be aware of?
Liquid biopsies using circulating tumor DNA (ctDNA) have shown promising results for cancer detection and management, including ovarian cancer. However, further clarification is needed to define the minimum tumor size/burden detectable using ctDNA-based approaches. Moreover, large prospective studies are needed to determine the clinical utility of ctDNA detection for early diagnosis of ovarian cancer and its impact on patient outcomes.
DNA methylation is an early event in carcinogenesis and can be detected in blood plasma samples from cancer patients. Data related to the discovery and validation of discriminated methylated DNA marker candidates extracted from ovarian cancer tissues were presented at the American Society of Clinical Oncology meeting this year. Findings were subsequently evaluated in plasma from women with and without ovarian cancer.
In addition to blood, peritoneal fluid and uterine lavage have been used to obtain cell pellets that are used for the identification of common mutant genes – TP53, BRCA1, and BRCA2. These body fluids have also been shown as the source of tumor-derived material that can be used to differentiate between ovarian cancer patients and healthy individuals.
Further studies are needed to determine the sensitivity and specificity of other noninvasive tests for the diagnosis of ovarian cancer.
The American Cancer Society issued a statement that the human papillomavirus (HPV) test is the preferred cervical cancer screening tool. Why do they prefer the HPV test over the Pap test?
The American Cancer Society recommends that cervical cancer testing (screening) begin at age 25 years. Women aged 25-65 years should have a primary HPV test every 5 years. If primary HPV testing is not available, screening may be done with either a co-test that combines an HPV test with a Pap test every 5 years or a Pap test alone every 3 years.
The HPV test is widely available. The cost of an HPV test is approximately $44 (unit cost, 2014 USD). The cost of a Pap test is approximately $30 (unit cost, 2014 USD).
The HPV test is preferred over cytologic testing (Pap) for several reasons.
Firstly, in well-designed studies, the sensitivity of a single Pap smear for detecting high-grade precancer of the cervix is around 50%, which is less than optimal for a cancer screening test. Sensitivity means the chance that, if you have the disease (in this case, high-grade precancer of the cervix), the test will detect it. In particular, cytology is known to have an even more limited ability to detect glandular precancers, which arise in the endocervical canal rather than on or in close proximity to the exterior surface of the cervix (ectocervix). Thus, HPV-based screening programs hold the promise of improving detection of cervical adenocarcinoma.
Secondly, to function reliably, cytology programs require substantial infrastructure, highly qualified human resources, and a well‐defined quality-control system, which have proved to be costly and difficult to implement. This results in global disparities in cytology-based cervical cancer screening programs.
Thirdly, although co‐testing with both cytology and HPV tests is an option for screening programs, studies have confirmed that there is limited benefit from adding cytology to HPV screening. Long‐term studies from Kaiser Permanente that included over 1 million women found that HPV testing has a very high negative predictive value for precancerous lesions. Women with negative HPV tests were very unlikely to develop precancerous lesions in the following 5 years. The 5‐year risk of high-grade precancer or cancer of the cervix following a negative HPV test was 0.14%, whereas for women with a negative cytology, it was 0.31%. The screening benefit of co‐testing is largely driven by HPV testing and not cytology.
So, in summary, HPV testing is preferred over cytologic screening for cervical cancer, given its improved sensitivity and quality assurance, the opportunity to automate testing, and ultimately, its prospect of reducing the overall number of lifetime screenings for women.
Dr. Stone has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Encouraging trends abound in the management of ovarian cancer. As rates of ovarian disease continue to decline, there has also been a notable increase in tools for detecting it earlier in its course.
To better understand these developments, this news organization reached out to Rebecca Stone, MD, an ovarian cancer expert and associate professor of gynecologic oncology at Johns Hopkins University, in Baltimore, Maryland. This interview has been edited for length and clarity.
There has been a decline in the rates of ovarian cancer in recent years. What are the possible causes of this?Dr. Stone: The number of new cases in the United States has actually been declining over the past 2 decades. This is thought to be attributable to the increased prescribing of oral contraceptive pills in the late 1990s and the uptake of preventive measures, such as risk-reducing gynecologic surgery for women with genetic predisposition to ovarian cancer, as well as opportunistic salpingectomy in the general population. Opportunistic salpingectomy was introduced about 10 years ago. It is a surgical means for primary prevention of tubo-ovarian cancer by removing both fallopian tubes at the time of elective surgery for women who have completed childbearing or in lieu of “tying the tubes” for women who desire permanent surgical sterility.
What can you tell us about a recent study suggesting that high-grade serous epithelial ovarian cancer may be detected earlier in the course of the disease by testing for TP53 clonal variants in DNA from Papanicolaou (Pap) tests performed during cervical cancer screening?
The idea here is that early mutational events that ultimately result in the development of epithelial ovarian cancer can be detected by performing gene sequencing on genetic material collected at the time of routine Pap smear screening done for cervical cancer. Pap tests are known to contain cells and genetic material shed from the fallopian tubes, where the precancerous lesions thought to give rise to epithelial ovarian cancer, predominantly serous epithelial ovarian cancers, start.
p53 gene mutations are thought to occur early in the evolution of ovarian cancer. There are data indicating that these mutations actually occur in cells lining the fallopian tubes. Polymerase chain reaction–based DNA/gene sequencing performed on cervical fluid collected by Pap smears could detect these p53-mutated cells shed from the fallopian tubes.
A strength of this study is that it included healthy controls. None of their Pap smears screened positive for the p53 mutations, unlike the Pap smears of women predating their diagnosis of ovarian cancer. Limitations of the study include the fact that it had a small sample size. Findings will need to be confirmed in a larger patient population.
Also, the study only looked for p53 gene mutations. Ovarian cancers, like other cancers, are largely thought to occur when there is a buildup of mutations in critical genes that result in uncontrolled cell growth and division. These genetic changes/mutations are acquired during a person’s lifetime. Thus, there are likely early genetic changes/mutations that occur in addition to p53 mutations that ultimately lead to the development of ovarian cancer. Detecting these along with p53 mutations could improve the sensitivity/detection rate of the screening strategy that the authors are investigating.
Finally, this screening strategy may not prove effective for the early detection of all histologic subtypes of epithelial ovarian cancer or for nonepithelial ovarian cancers.
What other recent developments in the diagnosis of ovarian cancer should clinicians be aware of?
Liquid biopsies using circulating tumor DNA (ctDNA) have shown promising results for cancer detection and management, including ovarian cancer. However, further clarification is needed to define the minimum tumor size/burden detectable using ctDNA-based approaches. Moreover, large prospective studies are needed to determine the clinical utility of ctDNA detection for early diagnosis of ovarian cancer and its impact on patient outcomes.
DNA methylation is an early event in carcinogenesis and can be detected in blood plasma samples from cancer patients. Data related to the discovery and validation of discriminated methylated DNA marker candidates extracted from ovarian cancer tissues were presented at the American Society of Clinical Oncology meeting this year. Findings were subsequently evaluated in plasma from women with and without ovarian cancer.
In addition to blood, peritoneal fluid and uterine lavage have been used to obtain cell pellets that are used for the identification of common mutant genes – TP53, BRCA1, and BRCA2. These body fluids have also been shown as the source of tumor-derived material that can be used to differentiate between ovarian cancer patients and healthy individuals.
Further studies are needed to determine the sensitivity and specificity of other noninvasive tests for the diagnosis of ovarian cancer.
The American Cancer Society issued a statement that the human papillomavirus (HPV) test is the preferred cervical cancer screening tool. Why do they prefer the HPV test over the Pap test?
The American Cancer Society recommends that cervical cancer testing (screening) begin at age 25 years. Women aged 25-65 years should have a primary HPV test every 5 years. If primary HPV testing is not available, screening may be done with either a co-test that combines an HPV test with a Pap test every 5 years or a Pap test alone every 3 years.
The HPV test is widely available. The cost of an HPV test is approximately $44 (unit cost, 2014 USD). The cost of a Pap test is approximately $30 (unit cost, 2014 USD).
The HPV test is preferred over cytologic testing (Pap) for several reasons.
Firstly, in well-designed studies, the sensitivity of a single Pap smear for detecting high-grade precancer of the cervix is around 50%, which is less than optimal for a cancer screening test. Sensitivity means the chance that, if you have the disease (in this case, high-grade precancer of the cervix), the test will detect it. In particular, cytology is known to have an even more limited ability to detect glandular precancers, which arise in the endocervical canal rather than on or in close proximity to the exterior surface of the cervix (ectocervix). Thus, HPV-based screening programs hold the promise of improving detection of cervical adenocarcinoma.
Secondly, to function reliably, cytology programs require substantial infrastructure, highly qualified human resources, and a well‐defined quality-control system, which have proved to be costly and difficult to implement. This results in global disparities in cytology-based cervical cancer screening programs.
Thirdly, although co‐testing with both cytology and HPV tests is an option for screening programs, studies have confirmed that there is limited benefit from adding cytology to HPV screening. Long‐term studies from Kaiser Permanente that included over 1 million women found that HPV testing has a very high negative predictive value for precancerous lesions. Women with negative HPV tests were very unlikely to develop precancerous lesions in the following 5 years. The 5‐year risk of high-grade precancer or cancer of the cervix following a negative HPV test was 0.14%, whereas for women with a negative cytology, it was 0.31%. The screening benefit of co‐testing is largely driven by HPV testing and not cytology.
So, in summary, HPV testing is preferred over cytologic screening for cervical cancer, given its improved sensitivity and quality assurance, the opportunity to automate testing, and ultimately, its prospect of reducing the overall number of lifetime screenings for women.
Dr. Stone has disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
Molecular features of medulloblastoma may help personalize radiotherapy
Results from this analysis were reported at the American Society for Radiation Oncology Annual Meeting 2020.
“Today, molecular diagnostics play a critical role in the classification of tumors, particularly medulloblastoma,” noted lead investigator Jeff M. Michalski, MD, of Washington University St. Louis, Mo.
“It is now recognized that medulloblastoma can be subgrouped into four distinct entities with unique demographics and tumor behaviors,” he said.
Those four groups are the SHH subgroup, the WNT subgroup, group 3, and group 4.
Study rationale and details
The benefits of current multimodality therapy in controlling and curing medulloblastoma come at the cost of toxicity, especially for younger patients, in terms of neurocognitive deficits, secondary cancers, and growth and neuro-endocrine abnormalities.
With this in mind, Dr. Michalski and colleagues conducted a phase 3 trial to test two strategies for reducing radiation in average-risk medulloblastoma without compromising outcomes.
After craniospinal irradiation (CSI), all patients were randomized to a radiation boost to the whole posterior fossa (PFRT) or an involved field volume (IFRT). Patients aged 8-21 years received CSI at the standard dose (23.4 Gy). Patients aged 3-7 years were randomized to standard-dose CSI or low-dose CSI (18 Gy).
There were 464 patients in whom PFRT to IFRT could be compared and 226 patients in whom standard and low-dose CSI could be compared.
Only 362 patients had sufficient tumor tissue to allow for classification into molecular subgroups. Among these patients, 43.1% fell into the group 4 subgroup, 21.0% into the group 3 subgroup, 18.2% into the SHH subgroup, and 17.7% into the WNT subgroup.
Survival results
The trial’s primary outcomes were event-free and overall survival. Events were defined as progression, recurrence, death, or second malignancy.
For the whole cohort, boost volume did not significantly affect outcomes. IFRT and PFRT yielded similar 5-year event-free survival (82.5% vs. 80.5%; P = .44) and overall survival (84.6% vs. 85.2%; P = .44). However, CSI dose did affect outcomes, with the low dose inferior to the standard dose on both 5-year event-free survival (71.4% vs. 82.9%; P = .028) and overall survival (77.5% vs. 85.6%; P = .049).
In analyses stratified by molecular subgroup, event-free survival did not differ significantly by boost volume within subgroups, except for the SHH subgroup, within which PFRT yielded worse outcomes (P = .018). Similarly, event-free survival did not differ significantly by CSI dose within subgroups, except for group 4, within which the low dose yielded a worse outcome (P = .047).
When specific genomic alterations were also considered, patients in the SHH group had worse outcomes if they had chromosome 14q loss, chromosome 10q loss, or p53 mutation. Patients in group 3 had worse outcomes if they had MYC amplification, iso-chromosome 17q, or both of these abnormalities.
No significant correlations were seen for group 4 patients, and there were too few patients in the WNT subgroup to assess correlations.
“Survival rates following reduced radiation boost volumes were comparable to standard treatment volumes for the primary tumor site. Interestingly, the SHH subgroup had worse event-free survival with whole posterior fossa radiation therapy,” Dr. Michalski commented. “Reduced dose of craniospinal axis irradiation was associated with higher event rates and worse survival, and group 4 was the primary subgroup that drove these inferior outcomes.”
“Specific genomic abnormalities are associated with worse outcomes, and future trials should consider subgroup and these genomic abnormalities in their study design,” he recommended.
‘A new era’ of risk stratification
Current evidence “leads us to conclude that certain molecular subgroups and specific genetic abnormalities within the subgroups are primary drivers of outcome and can be associated with far worse outcomes than what the conventional risk definition might suggest,” said invited discussant Stephanie Terezakis, MD, of the University of Minnesota in Minneapolis.
“In fact, differences in outcomes are greater between molecular subgroups and genomic abnormalities in large trial cohorts than between clinical trials when we use conventional risk definitions,” Dr. Terezakis said.
The ACNS0331 trial’s subgroup findings demonstrate that one size of therapy may not fit all, she elaborated. For example, some patients with favorable tumor biology may still be able to receive deintensified therapy and maintain excellent outcomes, whereas other patients with unfavorable tumor biology could potentially be newly classified as high risk and eligible for intensified therapy.
“This is the subject of ongoing discussions today to try to inform this next generation of trials, to see how we risk-stratify patients,” Dr. Terezakis concluded. “This model of conducting a national clinical trial with biologic endpoints has allowed us to usher in a new era where tumor biology may potentially guide our treatment approaches and lead to more personalized cancer care.”
The trial was funded by the National Cancer Institute, The Brain Tumor Charity, and St. Jude Children’s Research Hospital. Dr. Michalski disclosed relationships with ViewRay, Boston Scientific, Merck, and Blue Earth Diagnostics. Dr. Terezakis disclosed scientific grants from the Radiation Oncology Institute and the Sarcoma Foundation of America.
SOURCE: Michalski JM et al. ASTRO 2020, Abstract 1.
Results from this analysis were reported at the American Society for Radiation Oncology Annual Meeting 2020.
“Today, molecular diagnostics play a critical role in the classification of tumors, particularly medulloblastoma,” noted lead investigator Jeff M. Michalski, MD, of Washington University St. Louis, Mo.
“It is now recognized that medulloblastoma can be subgrouped into four distinct entities with unique demographics and tumor behaviors,” he said.
Those four groups are the SHH subgroup, the WNT subgroup, group 3, and group 4.
Study rationale and details
The benefits of current multimodality therapy in controlling and curing medulloblastoma come at the cost of toxicity, especially for younger patients, in terms of neurocognitive deficits, secondary cancers, and growth and neuro-endocrine abnormalities.
With this in mind, Dr. Michalski and colleagues conducted a phase 3 trial to test two strategies for reducing radiation in average-risk medulloblastoma without compromising outcomes.
After craniospinal irradiation (CSI), all patients were randomized to a radiation boost to the whole posterior fossa (PFRT) or an involved field volume (IFRT). Patients aged 8-21 years received CSI at the standard dose (23.4 Gy). Patients aged 3-7 years were randomized to standard-dose CSI or low-dose CSI (18 Gy).
There were 464 patients in whom PFRT to IFRT could be compared and 226 patients in whom standard and low-dose CSI could be compared.
Only 362 patients had sufficient tumor tissue to allow for classification into molecular subgroups. Among these patients, 43.1% fell into the group 4 subgroup, 21.0% into the group 3 subgroup, 18.2% into the SHH subgroup, and 17.7% into the WNT subgroup.
Survival results
The trial’s primary outcomes were event-free and overall survival. Events were defined as progression, recurrence, death, or second malignancy.
For the whole cohort, boost volume did not significantly affect outcomes. IFRT and PFRT yielded similar 5-year event-free survival (82.5% vs. 80.5%; P = .44) and overall survival (84.6% vs. 85.2%; P = .44). However, CSI dose did affect outcomes, with the low dose inferior to the standard dose on both 5-year event-free survival (71.4% vs. 82.9%; P = .028) and overall survival (77.5% vs. 85.6%; P = .049).
In analyses stratified by molecular subgroup, event-free survival did not differ significantly by boost volume within subgroups, except for the SHH subgroup, within which PFRT yielded worse outcomes (P = .018). Similarly, event-free survival did not differ significantly by CSI dose within subgroups, except for group 4, within which the low dose yielded a worse outcome (P = .047).
When specific genomic alterations were also considered, patients in the SHH group had worse outcomes if they had chromosome 14q loss, chromosome 10q loss, or p53 mutation. Patients in group 3 had worse outcomes if they had MYC amplification, iso-chromosome 17q, or both of these abnormalities.
No significant correlations were seen for group 4 patients, and there were too few patients in the WNT subgroup to assess correlations.
“Survival rates following reduced radiation boost volumes were comparable to standard treatment volumes for the primary tumor site. Interestingly, the SHH subgroup had worse event-free survival with whole posterior fossa radiation therapy,” Dr. Michalski commented. “Reduced dose of craniospinal axis irradiation was associated with higher event rates and worse survival, and group 4 was the primary subgroup that drove these inferior outcomes.”
“Specific genomic abnormalities are associated with worse outcomes, and future trials should consider subgroup and these genomic abnormalities in their study design,” he recommended.
‘A new era’ of risk stratification
Current evidence “leads us to conclude that certain molecular subgroups and specific genetic abnormalities within the subgroups are primary drivers of outcome and can be associated with far worse outcomes than what the conventional risk definition might suggest,” said invited discussant Stephanie Terezakis, MD, of the University of Minnesota in Minneapolis.
“In fact, differences in outcomes are greater between molecular subgroups and genomic abnormalities in large trial cohorts than between clinical trials when we use conventional risk definitions,” Dr. Terezakis said.
The ACNS0331 trial’s subgroup findings demonstrate that one size of therapy may not fit all, she elaborated. For example, some patients with favorable tumor biology may still be able to receive deintensified therapy and maintain excellent outcomes, whereas other patients with unfavorable tumor biology could potentially be newly classified as high risk and eligible for intensified therapy.
“This is the subject of ongoing discussions today to try to inform this next generation of trials, to see how we risk-stratify patients,” Dr. Terezakis concluded. “This model of conducting a national clinical trial with biologic endpoints has allowed us to usher in a new era where tumor biology may potentially guide our treatment approaches and lead to more personalized cancer care.”
The trial was funded by the National Cancer Institute, The Brain Tumor Charity, and St. Jude Children’s Research Hospital. Dr. Michalski disclosed relationships with ViewRay, Boston Scientific, Merck, and Blue Earth Diagnostics. Dr. Terezakis disclosed scientific grants from the Radiation Oncology Institute and the Sarcoma Foundation of America.
SOURCE: Michalski JM et al. ASTRO 2020, Abstract 1.
Results from this analysis were reported at the American Society for Radiation Oncology Annual Meeting 2020.
“Today, molecular diagnostics play a critical role in the classification of tumors, particularly medulloblastoma,” noted lead investigator Jeff M. Michalski, MD, of Washington University St. Louis, Mo.
“It is now recognized that medulloblastoma can be subgrouped into four distinct entities with unique demographics and tumor behaviors,” he said.
Those four groups are the SHH subgroup, the WNT subgroup, group 3, and group 4.
Study rationale and details
The benefits of current multimodality therapy in controlling and curing medulloblastoma come at the cost of toxicity, especially for younger patients, in terms of neurocognitive deficits, secondary cancers, and growth and neuro-endocrine abnormalities.
With this in mind, Dr. Michalski and colleagues conducted a phase 3 trial to test two strategies for reducing radiation in average-risk medulloblastoma without compromising outcomes.
After craniospinal irradiation (CSI), all patients were randomized to a radiation boost to the whole posterior fossa (PFRT) or an involved field volume (IFRT). Patients aged 8-21 years received CSI at the standard dose (23.4 Gy). Patients aged 3-7 years were randomized to standard-dose CSI or low-dose CSI (18 Gy).
There were 464 patients in whom PFRT to IFRT could be compared and 226 patients in whom standard and low-dose CSI could be compared.
Only 362 patients had sufficient tumor tissue to allow for classification into molecular subgroups. Among these patients, 43.1% fell into the group 4 subgroup, 21.0% into the group 3 subgroup, 18.2% into the SHH subgroup, and 17.7% into the WNT subgroup.
Survival results
The trial’s primary outcomes were event-free and overall survival. Events were defined as progression, recurrence, death, or second malignancy.
For the whole cohort, boost volume did not significantly affect outcomes. IFRT and PFRT yielded similar 5-year event-free survival (82.5% vs. 80.5%; P = .44) and overall survival (84.6% vs. 85.2%; P = .44). However, CSI dose did affect outcomes, with the low dose inferior to the standard dose on both 5-year event-free survival (71.4% vs. 82.9%; P = .028) and overall survival (77.5% vs. 85.6%; P = .049).
In analyses stratified by molecular subgroup, event-free survival did not differ significantly by boost volume within subgroups, except for the SHH subgroup, within which PFRT yielded worse outcomes (P = .018). Similarly, event-free survival did not differ significantly by CSI dose within subgroups, except for group 4, within which the low dose yielded a worse outcome (P = .047).
When specific genomic alterations were also considered, patients in the SHH group had worse outcomes if they had chromosome 14q loss, chromosome 10q loss, or p53 mutation. Patients in group 3 had worse outcomes if they had MYC amplification, iso-chromosome 17q, or both of these abnormalities.
No significant correlations were seen for group 4 patients, and there were too few patients in the WNT subgroup to assess correlations.
“Survival rates following reduced radiation boost volumes were comparable to standard treatment volumes for the primary tumor site. Interestingly, the SHH subgroup had worse event-free survival with whole posterior fossa radiation therapy,” Dr. Michalski commented. “Reduced dose of craniospinal axis irradiation was associated with higher event rates and worse survival, and group 4 was the primary subgroup that drove these inferior outcomes.”
“Specific genomic abnormalities are associated with worse outcomes, and future trials should consider subgroup and these genomic abnormalities in their study design,” he recommended.
‘A new era’ of risk stratification
Current evidence “leads us to conclude that certain molecular subgroups and specific genetic abnormalities within the subgroups are primary drivers of outcome and can be associated with far worse outcomes than what the conventional risk definition might suggest,” said invited discussant Stephanie Terezakis, MD, of the University of Minnesota in Minneapolis.
“In fact, differences in outcomes are greater between molecular subgroups and genomic abnormalities in large trial cohorts than between clinical trials when we use conventional risk definitions,” Dr. Terezakis said.
The ACNS0331 trial’s subgroup findings demonstrate that one size of therapy may not fit all, she elaborated. For example, some patients with favorable tumor biology may still be able to receive deintensified therapy and maintain excellent outcomes, whereas other patients with unfavorable tumor biology could potentially be newly classified as high risk and eligible for intensified therapy.
“This is the subject of ongoing discussions today to try to inform this next generation of trials, to see how we risk-stratify patients,” Dr. Terezakis concluded. “This model of conducting a national clinical trial with biologic endpoints has allowed us to usher in a new era where tumor biology may potentially guide our treatment approaches and lead to more personalized cancer care.”
The trial was funded by the National Cancer Institute, The Brain Tumor Charity, and St. Jude Children’s Research Hospital. Dr. Michalski disclosed relationships with ViewRay, Boston Scientific, Merck, and Blue Earth Diagnostics. Dr. Terezakis disclosed scientific grants from the Radiation Oncology Institute and the Sarcoma Foundation of America.
SOURCE: Michalski JM et al. ASTRO 2020, Abstract 1.
FROM ASTRO 2020
A guide to the new agents reshaping ovarian cancer treatment
The treatment of ovarian cancer has evolved considerably in the last few years, with the approval of several PARP inhibitors, antiangiogenic agents, and other therapies for a multitude of indications. Additional treatments are likely to soon join this already diverse spectrum of available options, if their promising efficacy and safety continues to be borne out in ongoing research.
To better understand the individual merits and potential drawbacks of these treatments, Medscape recently spoke with Rebecca Stone, MD, an ovarian cancer expert and associate professor of gynecologic oncology at Johns Hopkins University, Baltimore. This interview has been edited for length and clarity.
Medscape: We’re starting to see preliminary data on pamiparib , an investigational inhibitor of PARP1 and PARP2, for the treatment of ovarian cancer. What is the evidence supporting this drug?
Dr. Stone: Currently, six different PARP inhibitors – olaparib, rucaparib, veliparib, niraparib, talazoparib, and pamiparib – have been in clinical development at different stages. In clinical applications, PARP inhibitors, including olaparib, rucaparib, niraparib, and talazoparib, have demonstrated sustained antitumor responses as single agents in patients with BRCA1 or BRCA2 mutations. Those with Food and Drug Administration indications in ovarian cancer include olaparib, rucaparib, and niraparib. The preclinical and clinical data with pamiparib is limited as of now. But, in a xenograft breast cancer model, it was found to be over 10 times more potent than olaparib.
If approved, where would pamiparib fit in the treatment paradigm for ovarian cancer?
It would potentially fit as monotherapy as well as in combination with agents other than standard chemotherapy for the treatment of BRCA mutated ovarian cancer. It could also be considered for maintenance therapy at the conclusion of chemotherapy treatment of newly diagnosed or recurrent BRCA-mutated ovarian cancer.
What adverse events are associated with pamiparib? How does the toxicity profile compare with other drugs for ovarian cancer?
With respect to PARP inhibitors, the differences in potency (PARP trapping) correlate with their toxicity profiles. The most common adverse events are gastrointestinal, hematologic, and constitutional (fatigue). Even though it is difficult to compare toxicities across different trials with heterogeneous patient populations, there are a few points worth noting.
Rucaparib leads to inhibition of renal transporter proteins involved in secretion of creatinine and can lead to increased creatinine (any grade: 15%; grade 3: ≤1%). Transaminitis is generally self-limiting and highest with rucaparib (any grade: 34%; grade 3: 10%). Hematologic toxicities are the highest with niraparib (any grade: thrombocytopenia 61%, anemia 50%, neutropenia 30%; grade ≥3: thrombocytopenia 34%, anemia 25%, neutropenia 20%).
Toxicities are more common in the first few cycles of treatment, warranting closer early monitoring. This differs somewhat from the gastrointestinal, hematological, and constitutional (fatigue) adverse events that we see with common chemotherapeutic agents used to treat ovarian cancer, which are generally cumulative.
PARP inhibitor treatment is also associated with an increased risk of developing myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). That being said, therapy-related MDS/AML is a well-recognized complication of conventional chemotherapy used to treat a variety of primary malignancies, including ovarian cancer.
The expected toxicity profile for pamiparib is based on what we have seen with the other PARP inhibitors. This includes any grade nausea (50%), fatigue (33%), anemia (20%), vomiting (15%), and neutropenia (13%). Toxicity of grade 3 or higher includes anemia (13%), neutropenia (8%), and fatigue (5%).
Where do the newest drugs to be approved for ovarian cancer in recent years fit within the treatment paradigm? What do the research findings show about their efficacy and safety?
Data from phase 2/3 trials support the use of PARP inhibitors as monotherapy as well as in combination with other agents (most commonly agents other than standard chemotherapy) for the treatment of BRCA mutated or otherwise homologous recombination-deficient (HRD) ovarian cancer. They can also be considered for maintenance therapy at the conclusion of treatment of newly diagnosed or recurrent BRCA-mutated/HRD ovarian cancer.
Large phase 3 studies have resulted in the approval of the antiangiogenic agent bevacizumab in combination with chemotherapy for the treatment of newly diagnosed and recurrent ovarian cancer, as well as for maintenance therapy at the conclusion of combination chemotherapy plus bevacizumab treatment of newly diagnosed (GOG 218 and ICON 7 trials) or recurrent ovarian cancer (GOG 218, OCEANS, and AURELIA trials). The most common toxicity with antiangiogenic agents is hypertension. Women also commonly experience arthralgia/myalgia. There is an increased risk of proteinuria, blood clots, bleeding, and serious gastrointestinal events such as fistula and bowel perforation.
Data from the phase 2 KEYNOTE 158 trial support pembrolizumab for microsatellite high or mismatch repair-deficient ovarian cancers. Common side effects associated with the use of pembrolizumab include fatigue, itchy skin, diarrhea, nausea, decreased appetite, rash, fever, cough, difficulty breathing, musculoskeletal pain, constipation, and joint pain. Pembrolizumab can cause the immune system to attack normal organs and tissues in the body resulting in serious side effects, including inflammation of such organs as the lungs, colon, liver, endocrine glands, and kidneys.
Evidence for hormonal therapy (i.e., aromatase inhibitors like letrozole) for the treatment of newly diagnosed and recurrent low-grade serous/endometrioid epithelial ovarian cancer comes from largely retrospective cohort studies. A large phase 3 study, now enrolling, will examine if letrozole monotherapy/maintenance is non-inferior to intravenous paclitaxel/carboplatin and maintenance letrozole with respect to progression-free survival in women with stage II-IV primary low-grade serous carcinoma of the ovary or peritoneum after primary surgical cytoreduction.
Hormonal therapies are generally very well tolerated. Common side effects may include hot flashes, warmth or redness in the face or chest, headache, dizziness, weakness, bone pain, muscle or joint pain, swelling, weight gain, increased sweating, or increased cholesterol in the blood.
What other drugs are in development for ovarian cancer?
VEGF receptor tyrosine kinase inhibitors, such as cediranib, are in development. Anlotinib is another drug being investigated. It is a new multi-target tyrosine kinase inhibitor that targets VEGFR, PDGFR, and FGFR. Drugs targeting folate-alpha receptor, such as mirvetuximab, are under investigation, particularly for patients with high folate-alpha receptor membrane staining by immunohistochemistry. Drugs targeting cell cycle arrest, such as CDK4/6 inhibitors, are also being considered.
Can you provide some of the highlights of ovarian cancer research presented at this year’s American Society of Clinical Oncology meeting ?
My take is that we have gone from a monotonous landscape of platinum doublet chemotherapy to an exciting, diversified landscape over the past several years. All of this activity has driven median overall survival up from 3 years to 5 years and progression-free survival following first platinum sensitive recurrence to well beyond 6 months.
Since last year’s meeting, we have seen several new approvals, including niraparib for the treatment of BRCA mutated and HRD disease, as well as for first-line maintenance in all comers. In May, the FDA expanded the indication for olaparib to include its combination with bevacizumab as first-line maintenance for BRCA-mutated and HRD disease based on the results of PAOLA-1. With certainty, our treatment paradigms will continue to evolve in response to these and other new data.
At this year’s meeting, the SOLO-2 investigators revealed the first overall survival data for second-line PARP inhibitor maintenance, which is the first suggestion that PARP inhibitor maintenance improves overall survival.
We have a new understanding about the genetics of long-term responders to rucaparib on ARIEL-2.
We also understand how the role of secondary cytoreductive surgery and how nonchemotherapy options for the treatment of platinum sensitive relapse compare in terms of efficacy and toxicity (i.e., AVANOVA-2 and GY004 trials). We see again the importance of R0 cytoreduction when surgery is pursued. Achieving anything less than R0 cytoreduction for the treatment of first platinum sensitive recurrence may translate into shorter survival, compared with chemotherapy alone.
We are also becoming increasingly familiar with the limited therapeutic benefit of single-agent anti-PD-1/PD-L1, which is so different from our experience in mismatch repair-deficient endometrial cancer. In the small percentage of responders, there are some durable responses and a suggestion of particular efficacy among women with clear cell ovarian cancer.
What other recent findings in ovarian cancer research should oncologists be aware of?
Data supporting improved efficacy of a gastrointestinal-type chemotherapy regimen for mucinous epithelial ovarian cancers come from a retrospective cohort study of patients with ovarian mucinous carcinoma who received postoperative adjuvant chemotherapy at two academic centers.
Identification of inactivating SMARCA4 mutations as the driver of small cell carcinoma of the ovary, hypercalcemic type, and the idea that CDK4/6 inhibitors could be effectively repurposed to treat this rare but highly aggressive type of ovarian cancer is also new and exciting.
Dr. Stone has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
The treatment of ovarian cancer has evolved considerably in the last few years, with the approval of several PARP inhibitors, antiangiogenic agents, and other therapies for a multitude of indications. Additional treatments are likely to soon join this already diverse spectrum of available options, if their promising efficacy and safety continues to be borne out in ongoing research.
To better understand the individual merits and potential drawbacks of these treatments, Medscape recently spoke with Rebecca Stone, MD, an ovarian cancer expert and associate professor of gynecologic oncology at Johns Hopkins University, Baltimore. This interview has been edited for length and clarity.
Medscape: We’re starting to see preliminary data on pamiparib , an investigational inhibitor of PARP1 and PARP2, for the treatment of ovarian cancer. What is the evidence supporting this drug?
Dr. Stone: Currently, six different PARP inhibitors – olaparib, rucaparib, veliparib, niraparib, talazoparib, and pamiparib – have been in clinical development at different stages. In clinical applications, PARP inhibitors, including olaparib, rucaparib, niraparib, and talazoparib, have demonstrated sustained antitumor responses as single agents in patients with BRCA1 or BRCA2 mutations. Those with Food and Drug Administration indications in ovarian cancer include olaparib, rucaparib, and niraparib. The preclinical and clinical data with pamiparib is limited as of now. But, in a xenograft breast cancer model, it was found to be over 10 times more potent than olaparib.
If approved, where would pamiparib fit in the treatment paradigm for ovarian cancer?
It would potentially fit as monotherapy as well as in combination with agents other than standard chemotherapy for the treatment of BRCA mutated ovarian cancer. It could also be considered for maintenance therapy at the conclusion of chemotherapy treatment of newly diagnosed or recurrent BRCA-mutated ovarian cancer.
What adverse events are associated with pamiparib? How does the toxicity profile compare with other drugs for ovarian cancer?
With respect to PARP inhibitors, the differences in potency (PARP trapping) correlate with their toxicity profiles. The most common adverse events are gastrointestinal, hematologic, and constitutional (fatigue). Even though it is difficult to compare toxicities across different trials with heterogeneous patient populations, there are a few points worth noting.
Rucaparib leads to inhibition of renal transporter proteins involved in secretion of creatinine and can lead to increased creatinine (any grade: 15%; grade 3: ≤1%). Transaminitis is generally self-limiting and highest with rucaparib (any grade: 34%; grade 3: 10%). Hematologic toxicities are the highest with niraparib (any grade: thrombocytopenia 61%, anemia 50%, neutropenia 30%; grade ≥3: thrombocytopenia 34%, anemia 25%, neutropenia 20%).
Toxicities are more common in the first few cycles of treatment, warranting closer early monitoring. This differs somewhat from the gastrointestinal, hematological, and constitutional (fatigue) adverse events that we see with common chemotherapeutic agents used to treat ovarian cancer, which are generally cumulative.
PARP inhibitor treatment is also associated with an increased risk of developing myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). That being said, therapy-related MDS/AML is a well-recognized complication of conventional chemotherapy used to treat a variety of primary malignancies, including ovarian cancer.
The expected toxicity profile for pamiparib is based on what we have seen with the other PARP inhibitors. This includes any grade nausea (50%), fatigue (33%), anemia (20%), vomiting (15%), and neutropenia (13%). Toxicity of grade 3 or higher includes anemia (13%), neutropenia (8%), and fatigue (5%).
Where do the newest drugs to be approved for ovarian cancer in recent years fit within the treatment paradigm? What do the research findings show about their efficacy and safety?
Data from phase 2/3 trials support the use of PARP inhibitors as monotherapy as well as in combination with other agents (most commonly agents other than standard chemotherapy) for the treatment of BRCA mutated or otherwise homologous recombination-deficient (HRD) ovarian cancer. They can also be considered for maintenance therapy at the conclusion of treatment of newly diagnosed or recurrent BRCA-mutated/HRD ovarian cancer.
Large phase 3 studies have resulted in the approval of the antiangiogenic agent bevacizumab in combination with chemotherapy for the treatment of newly diagnosed and recurrent ovarian cancer, as well as for maintenance therapy at the conclusion of combination chemotherapy plus bevacizumab treatment of newly diagnosed (GOG 218 and ICON 7 trials) or recurrent ovarian cancer (GOG 218, OCEANS, and AURELIA trials). The most common toxicity with antiangiogenic agents is hypertension. Women also commonly experience arthralgia/myalgia. There is an increased risk of proteinuria, blood clots, bleeding, and serious gastrointestinal events such as fistula and bowel perforation.
Data from the phase 2 KEYNOTE 158 trial support pembrolizumab for microsatellite high or mismatch repair-deficient ovarian cancers. Common side effects associated with the use of pembrolizumab include fatigue, itchy skin, diarrhea, nausea, decreased appetite, rash, fever, cough, difficulty breathing, musculoskeletal pain, constipation, and joint pain. Pembrolizumab can cause the immune system to attack normal organs and tissues in the body resulting in serious side effects, including inflammation of such organs as the lungs, colon, liver, endocrine glands, and kidneys.
Evidence for hormonal therapy (i.e., aromatase inhibitors like letrozole) for the treatment of newly diagnosed and recurrent low-grade serous/endometrioid epithelial ovarian cancer comes from largely retrospective cohort studies. A large phase 3 study, now enrolling, will examine if letrozole monotherapy/maintenance is non-inferior to intravenous paclitaxel/carboplatin and maintenance letrozole with respect to progression-free survival in women with stage II-IV primary low-grade serous carcinoma of the ovary or peritoneum after primary surgical cytoreduction.
Hormonal therapies are generally very well tolerated. Common side effects may include hot flashes, warmth or redness in the face or chest, headache, dizziness, weakness, bone pain, muscle or joint pain, swelling, weight gain, increased sweating, or increased cholesterol in the blood.
What other drugs are in development for ovarian cancer?
VEGF receptor tyrosine kinase inhibitors, such as cediranib, are in development. Anlotinib is another drug being investigated. It is a new multi-target tyrosine kinase inhibitor that targets VEGFR, PDGFR, and FGFR. Drugs targeting folate-alpha receptor, such as mirvetuximab, are under investigation, particularly for patients with high folate-alpha receptor membrane staining by immunohistochemistry. Drugs targeting cell cycle arrest, such as CDK4/6 inhibitors, are also being considered.
Can you provide some of the highlights of ovarian cancer research presented at this year’s American Society of Clinical Oncology meeting ?
My take is that we have gone from a monotonous landscape of platinum doublet chemotherapy to an exciting, diversified landscape over the past several years. All of this activity has driven median overall survival up from 3 years to 5 years and progression-free survival following first platinum sensitive recurrence to well beyond 6 months.
Since last year’s meeting, we have seen several new approvals, including niraparib for the treatment of BRCA mutated and HRD disease, as well as for first-line maintenance in all comers. In May, the FDA expanded the indication for olaparib to include its combination with bevacizumab as first-line maintenance for BRCA-mutated and HRD disease based on the results of PAOLA-1. With certainty, our treatment paradigms will continue to evolve in response to these and other new data.
At this year’s meeting, the SOLO-2 investigators revealed the first overall survival data for second-line PARP inhibitor maintenance, which is the first suggestion that PARP inhibitor maintenance improves overall survival.
We have a new understanding about the genetics of long-term responders to rucaparib on ARIEL-2.
We also understand how the role of secondary cytoreductive surgery and how nonchemotherapy options for the treatment of platinum sensitive relapse compare in terms of efficacy and toxicity (i.e., AVANOVA-2 and GY004 trials). We see again the importance of R0 cytoreduction when surgery is pursued. Achieving anything less than R0 cytoreduction for the treatment of first platinum sensitive recurrence may translate into shorter survival, compared with chemotherapy alone.
We are also becoming increasingly familiar with the limited therapeutic benefit of single-agent anti-PD-1/PD-L1, which is so different from our experience in mismatch repair-deficient endometrial cancer. In the small percentage of responders, there are some durable responses and a suggestion of particular efficacy among women with clear cell ovarian cancer.
What other recent findings in ovarian cancer research should oncologists be aware of?
Data supporting improved efficacy of a gastrointestinal-type chemotherapy regimen for mucinous epithelial ovarian cancers come from a retrospective cohort study of patients with ovarian mucinous carcinoma who received postoperative adjuvant chemotherapy at two academic centers.
Identification of inactivating SMARCA4 mutations as the driver of small cell carcinoma of the ovary, hypercalcemic type, and the idea that CDK4/6 inhibitors could be effectively repurposed to treat this rare but highly aggressive type of ovarian cancer is also new and exciting.
Dr. Stone has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
The treatment of ovarian cancer has evolved considerably in the last few years, with the approval of several PARP inhibitors, antiangiogenic agents, and other therapies for a multitude of indications. Additional treatments are likely to soon join this already diverse spectrum of available options, if their promising efficacy and safety continues to be borne out in ongoing research.
To better understand the individual merits and potential drawbacks of these treatments, Medscape recently spoke with Rebecca Stone, MD, an ovarian cancer expert and associate professor of gynecologic oncology at Johns Hopkins University, Baltimore. This interview has been edited for length and clarity.
Medscape: We’re starting to see preliminary data on pamiparib , an investigational inhibitor of PARP1 and PARP2, for the treatment of ovarian cancer. What is the evidence supporting this drug?
Dr. Stone: Currently, six different PARP inhibitors – olaparib, rucaparib, veliparib, niraparib, talazoparib, and pamiparib – have been in clinical development at different stages. In clinical applications, PARP inhibitors, including olaparib, rucaparib, niraparib, and talazoparib, have demonstrated sustained antitumor responses as single agents in patients with BRCA1 or BRCA2 mutations. Those with Food and Drug Administration indications in ovarian cancer include olaparib, rucaparib, and niraparib. The preclinical and clinical data with pamiparib is limited as of now. But, in a xenograft breast cancer model, it was found to be over 10 times more potent than olaparib.
If approved, where would pamiparib fit in the treatment paradigm for ovarian cancer?
It would potentially fit as monotherapy as well as in combination with agents other than standard chemotherapy for the treatment of BRCA mutated ovarian cancer. It could also be considered for maintenance therapy at the conclusion of chemotherapy treatment of newly diagnosed or recurrent BRCA-mutated ovarian cancer.
What adverse events are associated with pamiparib? How does the toxicity profile compare with other drugs for ovarian cancer?
With respect to PARP inhibitors, the differences in potency (PARP trapping) correlate with their toxicity profiles. The most common adverse events are gastrointestinal, hematologic, and constitutional (fatigue). Even though it is difficult to compare toxicities across different trials with heterogeneous patient populations, there are a few points worth noting.
Rucaparib leads to inhibition of renal transporter proteins involved in secretion of creatinine and can lead to increased creatinine (any grade: 15%; grade 3: ≤1%). Transaminitis is generally self-limiting and highest with rucaparib (any grade: 34%; grade 3: 10%). Hematologic toxicities are the highest with niraparib (any grade: thrombocytopenia 61%, anemia 50%, neutropenia 30%; grade ≥3: thrombocytopenia 34%, anemia 25%, neutropenia 20%).
Toxicities are more common in the first few cycles of treatment, warranting closer early monitoring. This differs somewhat from the gastrointestinal, hematological, and constitutional (fatigue) adverse events that we see with common chemotherapeutic agents used to treat ovarian cancer, which are generally cumulative.
PARP inhibitor treatment is also associated with an increased risk of developing myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). That being said, therapy-related MDS/AML is a well-recognized complication of conventional chemotherapy used to treat a variety of primary malignancies, including ovarian cancer.
The expected toxicity profile for pamiparib is based on what we have seen with the other PARP inhibitors. This includes any grade nausea (50%), fatigue (33%), anemia (20%), vomiting (15%), and neutropenia (13%). Toxicity of grade 3 or higher includes anemia (13%), neutropenia (8%), and fatigue (5%).
Where do the newest drugs to be approved for ovarian cancer in recent years fit within the treatment paradigm? What do the research findings show about their efficacy and safety?
Data from phase 2/3 trials support the use of PARP inhibitors as monotherapy as well as in combination with other agents (most commonly agents other than standard chemotherapy) for the treatment of BRCA mutated or otherwise homologous recombination-deficient (HRD) ovarian cancer. They can also be considered for maintenance therapy at the conclusion of treatment of newly diagnosed or recurrent BRCA-mutated/HRD ovarian cancer.
Large phase 3 studies have resulted in the approval of the antiangiogenic agent bevacizumab in combination with chemotherapy for the treatment of newly diagnosed and recurrent ovarian cancer, as well as for maintenance therapy at the conclusion of combination chemotherapy plus bevacizumab treatment of newly diagnosed (GOG 218 and ICON 7 trials) or recurrent ovarian cancer (GOG 218, OCEANS, and AURELIA trials). The most common toxicity with antiangiogenic agents is hypertension. Women also commonly experience arthralgia/myalgia. There is an increased risk of proteinuria, blood clots, bleeding, and serious gastrointestinal events such as fistula and bowel perforation.
Data from the phase 2 KEYNOTE 158 trial support pembrolizumab for microsatellite high or mismatch repair-deficient ovarian cancers. Common side effects associated with the use of pembrolizumab include fatigue, itchy skin, diarrhea, nausea, decreased appetite, rash, fever, cough, difficulty breathing, musculoskeletal pain, constipation, and joint pain. Pembrolizumab can cause the immune system to attack normal organs and tissues in the body resulting in serious side effects, including inflammation of such organs as the lungs, colon, liver, endocrine glands, and kidneys.
Evidence for hormonal therapy (i.e., aromatase inhibitors like letrozole) for the treatment of newly diagnosed and recurrent low-grade serous/endometrioid epithelial ovarian cancer comes from largely retrospective cohort studies. A large phase 3 study, now enrolling, will examine if letrozole monotherapy/maintenance is non-inferior to intravenous paclitaxel/carboplatin and maintenance letrozole with respect to progression-free survival in women with stage II-IV primary low-grade serous carcinoma of the ovary or peritoneum after primary surgical cytoreduction.
Hormonal therapies are generally very well tolerated. Common side effects may include hot flashes, warmth or redness in the face or chest, headache, dizziness, weakness, bone pain, muscle or joint pain, swelling, weight gain, increased sweating, or increased cholesterol in the blood.
What other drugs are in development for ovarian cancer?
VEGF receptor tyrosine kinase inhibitors, such as cediranib, are in development. Anlotinib is another drug being investigated. It is a new multi-target tyrosine kinase inhibitor that targets VEGFR, PDGFR, and FGFR. Drugs targeting folate-alpha receptor, such as mirvetuximab, are under investigation, particularly for patients with high folate-alpha receptor membrane staining by immunohistochemistry. Drugs targeting cell cycle arrest, such as CDK4/6 inhibitors, are also being considered.
Can you provide some of the highlights of ovarian cancer research presented at this year’s American Society of Clinical Oncology meeting ?
My take is that we have gone from a monotonous landscape of platinum doublet chemotherapy to an exciting, diversified landscape over the past several years. All of this activity has driven median overall survival up from 3 years to 5 years and progression-free survival following first platinum sensitive recurrence to well beyond 6 months.
Since last year’s meeting, we have seen several new approvals, including niraparib for the treatment of BRCA mutated and HRD disease, as well as for first-line maintenance in all comers. In May, the FDA expanded the indication for olaparib to include its combination with bevacizumab as first-line maintenance for BRCA-mutated and HRD disease based on the results of PAOLA-1. With certainty, our treatment paradigms will continue to evolve in response to these and other new data.
At this year’s meeting, the SOLO-2 investigators revealed the first overall survival data for second-line PARP inhibitor maintenance, which is the first suggestion that PARP inhibitor maintenance improves overall survival.
We have a new understanding about the genetics of long-term responders to rucaparib on ARIEL-2.
We also understand how the role of secondary cytoreductive surgery and how nonchemotherapy options for the treatment of platinum sensitive relapse compare in terms of efficacy and toxicity (i.e., AVANOVA-2 and GY004 trials). We see again the importance of R0 cytoreduction when surgery is pursued. Achieving anything less than R0 cytoreduction for the treatment of first platinum sensitive recurrence may translate into shorter survival, compared with chemotherapy alone.
We are also becoming increasingly familiar with the limited therapeutic benefit of single-agent anti-PD-1/PD-L1, which is so different from our experience in mismatch repair-deficient endometrial cancer. In the small percentage of responders, there are some durable responses and a suggestion of particular efficacy among women with clear cell ovarian cancer.
What other recent findings in ovarian cancer research should oncologists be aware of?
Data supporting improved efficacy of a gastrointestinal-type chemotherapy regimen for mucinous epithelial ovarian cancers come from a retrospective cohort study of patients with ovarian mucinous carcinoma who received postoperative adjuvant chemotherapy at two academic centers.
Identification of inactivating SMARCA4 mutations as the driver of small cell carcinoma of the ovary, hypercalcemic type, and the idea that CDK4/6 inhibitors could be effectively repurposed to treat this rare but highly aggressive type of ovarian cancer is also new and exciting.
Dr. Stone has disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
No benefit with adjuvant sorafenib in intermediate-/high-risk RCC
“The results of the SORCE trial will end the debate about adjuvant tyrosine kinase inhibitors in renal cell carcinoma for most investigators,” Tim Eisen, MBBChir, PhD, of Cambridge (England) University Hospitals NHS Foundation Trust, said in an interview.
Dr. Eisen and colleagues reported results from SORCE in the Journal of Clinical Oncology.
Patients with intermediate- or high-risk RCC after surgical resection have 5-year relapse rates of 30%-40% and 5-year survival of 74.8% that declines steeply to 16% with metastatic disease, Dr. Eisen and colleagues wrote.
While adjuvant strategies – including cytokines, radiotherapy, and hormone therapy – have not yielded success, oral tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor have shown efficacy in metastatic RCC.
With inconsistent results in randomized trials of TKIs in the adjuvant RCC setting, however, active surveillance after nephrectomy has remained the international standard of care. SORCE was conducted “to settle the question of adjuvant TKI therapy” in RCC, according to Dr. Eisen and colleagues.
The investigators enrolled 1,711 patients with completely resected, clear cell or non–clear cell RCC at intermediate or high risk of relapse. The patients’ mean age was 58 years, 71% of patients were men, and 84% had clear cell histology.
Patients were randomized (2:3:3) to 3 years of placebo, 1 year of sorafenib followed by 2 years of placebo, or 3 years of sorafenib.
The initial sorafenib dose was 400 mg twice per day orally, but it was amended to 400 mg daily.
The primary outcome was investigator-reported disease-free survival comparing 3 years of sorafenib with placebo.
No survival benefit, more adverse events
Survival outcomes were similar across the study arms. The median disease-free survival was not reached for 3 years of sorafenib or for 3 years of placebo (hazard ratio, 1.01; 95% confidence interval, 0.82-1.23; P = .946).
The restricted mean survival time over 10 years was 6.81 years for 3 years of sorafenib and 6.82 years for 3 years of placebo (P = .988).
As for overall survival, the hazard ratio for 3 years of sorafenib versus 3 years of placebo was 1.06 (95% CI, 0.82-1.38; P = .638), and the hazard ratio for 1 year of sorafenib versus 3 years of placebo was 0.92 (95% CI, 0.71-1.20; P = .541).
Adverse events of grade 3 or higher were reported by 58.6% of patients receiving 1 year of sorafenib, 63.9% of patients receiving 3 years of sorafenib, and 29.2% of patients receiving placebo. Serious adverse events were reported at rates of 19.1% for placebo, 21.6% for 1 year of sorafenib, and 24% for 3 years of sorafenib.
Despite being offered treatment adaptations, more than half of participants had stopped treatment by 12 months because of toxicity.
Results undermine TKI use
“The significant toxicity observed with TKI monotherapy, despite pragmatic dose reductions, together with lack of evidence of a survival benefit, fundamentally undermines the use of TKIs in the adjuvant treatment of RCC,” Dr. Eisen and colleagues concluded.
In an interview, Dr. Eisen noted: “We are now asking whether adjuvant PD-1/PD-L1, with or without CTLA4 checkpoint inhibitors, are of benefit for patients who have had a high- or intermediate-risk RCC resected. A more challenging question is whether neoadjuvant checkpoint inhibitors may add further benefit. There are many such studies, which will report over the next few years and have the potential to change the treatment landscape enormously.”
“Interest in the field in general has shifted to immunotherapy and immunotherapy/TKI combinations,” observed Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute in Bethesda, Md., who was not involved in this study.
“The majority in the field probably had a fairly good idea that sorafenib was unlikely to show any benefit, whether given over 1 or 3 years. SORCE results were not unexpected. They do cement our belief that TKIs such as sorafenib do not have a real role in managing patients with kidney cancer in the adjuvant setting,” Dr. Srinivasan said.
The SORCE trial was supported by Bayer, Cancer Research UK, the Medical Research Council, University College London, Cancer Australia, and the Australian National Health and Medical Research Council. Dr. Eisen disclosed relationships with AstraZeneca, Roche, EUSA, Bayer, Pfizer, Macmillan Cancer Support, and Kidney Cancer UK. His coauthors disclosed relationships with many companies. Dr. Srinivasan disclosed that the National Cancer Institute has received funds from Calithera Biosciences and Peloton/Merck for clinical trials on which he was the principal investigator.
SOURCE: Eisen T et al. J Clin Oncol. 2020 Oct 14. J Clin Oncol. 2020 Oct 14. doi: 10.1200/JCO.20.01800.
“The results of the SORCE trial will end the debate about adjuvant tyrosine kinase inhibitors in renal cell carcinoma for most investigators,” Tim Eisen, MBBChir, PhD, of Cambridge (England) University Hospitals NHS Foundation Trust, said in an interview.
Dr. Eisen and colleagues reported results from SORCE in the Journal of Clinical Oncology.
Patients with intermediate- or high-risk RCC after surgical resection have 5-year relapse rates of 30%-40% and 5-year survival of 74.8% that declines steeply to 16% with metastatic disease, Dr. Eisen and colleagues wrote.
While adjuvant strategies – including cytokines, radiotherapy, and hormone therapy – have not yielded success, oral tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor have shown efficacy in metastatic RCC.
With inconsistent results in randomized trials of TKIs in the adjuvant RCC setting, however, active surveillance after nephrectomy has remained the international standard of care. SORCE was conducted “to settle the question of adjuvant TKI therapy” in RCC, according to Dr. Eisen and colleagues.
The investigators enrolled 1,711 patients with completely resected, clear cell or non–clear cell RCC at intermediate or high risk of relapse. The patients’ mean age was 58 years, 71% of patients were men, and 84% had clear cell histology.
Patients were randomized (2:3:3) to 3 years of placebo, 1 year of sorafenib followed by 2 years of placebo, or 3 years of sorafenib.
The initial sorafenib dose was 400 mg twice per day orally, but it was amended to 400 mg daily.
The primary outcome was investigator-reported disease-free survival comparing 3 years of sorafenib with placebo.
No survival benefit, more adverse events
Survival outcomes were similar across the study arms. The median disease-free survival was not reached for 3 years of sorafenib or for 3 years of placebo (hazard ratio, 1.01; 95% confidence interval, 0.82-1.23; P = .946).
The restricted mean survival time over 10 years was 6.81 years for 3 years of sorafenib and 6.82 years for 3 years of placebo (P = .988).
As for overall survival, the hazard ratio for 3 years of sorafenib versus 3 years of placebo was 1.06 (95% CI, 0.82-1.38; P = .638), and the hazard ratio for 1 year of sorafenib versus 3 years of placebo was 0.92 (95% CI, 0.71-1.20; P = .541).
Adverse events of grade 3 or higher were reported by 58.6% of patients receiving 1 year of sorafenib, 63.9% of patients receiving 3 years of sorafenib, and 29.2% of patients receiving placebo. Serious adverse events were reported at rates of 19.1% for placebo, 21.6% for 1 year of sorafenib, and 24% for 3 years of sorafenib.
Despite being offered treatment adaptations, more than half of participants had stopped treatment by 12 months because of toxicity.
Results undermine TKI use
“The significant toxicity observed with TKI monotherapy, despite pragmatic dose reductions, together with lack of evidence of a survival benefit, fundamentally undermines the use of TKIs in the adjuvant treatment of RCC,” Dr. Eisen and colleagues concluded.
In an interview, Dr. Eisen noted: “We are now asking whether adjuvant PD-1/PD-L1, with or without CTLA4 checkpoint inhibitors, are of benefit for patients who have had a high- or intermediate-risk RCC resected. A more challenging question is whether neoadjuvant checkpoint inhibitors may add further benefit. There are many such studies, which will report over the next few years and have the potential to change the treatment landscape enormously.”
“Interest in the field in general has shifted to immunotherapy and immunotherapy/TKI combinations,” observed Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute in Bethesda, Md., who was not involved in this study.
“The majority in the field probably had a fairly good idea that sorafenib was unlikely to show any benefit, whether given over 1 or 3 years. SORCE results were not unexpected. They do cement our belief that TKIs such as sorafenib do not have a real role in managing patients with kidney cancer in the adjuvant setting,” Dr. Srinivasan said.
The SORCE trial was supported by Bayer, Cancer Research UK, the Medical Research Council, University College London, Cancer Australia, and the Australian National Health and Medical Research Council. Dr. Eisen disclosed relationships with AstraZeneca, Roche, EUSA, Bayer, Pfizer, Macmillan Cancer Support, and Kidney Cancer UK. His coauthors disclosed relationships with many companies. Dr. Srinivasan disclosed that the National Cancer Institute has received funds from Calithera Biosciences and Peloton/Merck for clinical trials on which he was the principal investigator.
SOURCE: Eisen T et al. J Clin Oncol. 2020 Oct 14. J Clin Oncol. 2020 Oct 14. doi: 10.1200/JCO.20.01800.
“The results of the SORCE trial will end the debate about adjuvant tyrosine kinase inhibitors in renal cell carcinoma for most investigators,” Tim Eisen, MBBChir, PhD, of Cambridge (England) University Hospitals NHS Foundation Trust, said in an interview.
Dr. Eisen and colleagues reported results from SORCE in the Journal of Clinical Oncology.
Patients with intermediate- or high-risk RCC after surgical resection have 5-year relapse rates of 30%-40% and 5-year survival of 74.8% that declines steeply to 16% with metastatic disease, Dr. Eisen and colleagues wrote.
While adjuvant strategies – including cytokines, radiotherapy, and hormone therapy – have not yielded success, oral tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor have shown efficacy in metastatic RCC.
With inconsistent results in randomized trials of TKIs in the adjuvant RCC setting, however, active surveillance after nephrectomy has remained the international standard of care. SORCE was conducted “to settle the question of adjuvant TKI therapy” in RCC, according to Dr. Eisen and colleagues.
The investigators enrolled 1,711 patients with completely resected, clear cell or non–clear cell RCC at intermediate or high risk of relapse. The patients’ mean age was 58 years, 71% of patients were men, and 84% had clear cell histology.
Patients were randomized (2:3:3) to 3 years of placebo, 1 year of sorafenib followed by 2 years of placebo, or 3 years of sorafenib.
The initial sorafenib dose was 400 mg twice per day orally, but it was amended to 400 mg daily.
The primary outcome was investigator-reported disease-free survival comparing 3 years of sorafenib with placebo.
No survival benefit, more adverse events
Survival outcomes were similar across the study arms. The median disease-free survival was not reached for 3 years of sorafenib or for 3 years of placebo (hazard ratio, 1.01; 95% confidence interval, 0.82-1.23; P = .946).
The restricted mean survival time over 10 years was 6.81 years for 3 years of sorafenib and 6.82 years for 3 years of placebo (P = .988).
As for overall survival, the hazard ratio for 3 years of sorafenib versus 3 years of placebo was 1.06 (95% CI, 0.82-1.38; P = .638), and the hazard ratio for 1 year of sorafenib versus 3 years of placebo was 0.92 (95% CI, 0.71-1.20; P = .541).
Adverse events of grade 3 or higher were reported by 58.6% of patients receiving 1 year of sorafenib, 63.9% of patients receiving 3 years of sorafenib, and 29.2% of patients receiving placebo. Serious adverse events were reported at rates of 19.1% for placebo, 21.6% for 1 year of sorafenib, and 24% for 3 years of sorafenib.
Despite being offered treatment adaptations, more than half of participants had stopped treatment by 12 months because of toxicity.
Results undermine TKI use
“The significant toxicity observed with TKI monotherapy, despite pragmatic dose reductions, together with lack of evidence of a survival benefit, fundamentally undermines the use of TKIs in the adjuvant treatment of RCC,” Dr. Eisen and colleagues concluded.
In an interview, Dr. Eisen noted: “We are now asking whether adjuvant PD-1/PD-L1, with or without CTLA4 checkpoint inhibitors, are of benefit for patients who have had a high- or intermediate-risk RCC resected. A more challenging question is whether neoadjuvant checkpoint inhibitors may add further benefit. There are many such studies, which will report over the next few years and have the potential to change the treatment landscape enormously.”
“Interest in the field in general has shifted to immunotherapy and immunotherapy/TKI combinations,” observed Ramaprasad Srinivasan, MD, PhD, of the National Cancer Institute in Bethesda, Md., who was not involved in this study.
“The majority in the field probably had a fairly good idea that sorafenib was unlikely to show any benefit, whether given over 1 or 3 years. SORCE results were not unexpected. They do cement our belief that TKIs such as sorafenib do not have a real role in managing patients with kidney cancer in the adjuvant setting,” Dr. Srinivasan said.
The SORCE trial was supported by Bayer, Cancer Research UK, the Medical Research Council, University College London, Cancer Australia, and the Australian National Health and Medical Research Council. Dr. Eisen disclosed relationships with AstraZeneca, Roche, EUSA, Bayer, Pfizer, Macmillan Cancer Support, and Kidney Cancer UK. His coauthors disclosed relationships with many companies. Dr. Srinivasan disclosed that the National Cancer Institute has received funds from Calithera Biosciences and Peloton/Merck for clinical trials on which he was the principal investigator.
SOURCE: Eisen T et al. J Clin Oncol. 2020 Oct 14. J Clin Oncol. 2020 Oct 14. doi: 10.1200/JCO.20.01800.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
COMPARE CRUSH: Crushed prehospital prasugrel misses mark in STEMI
Giving crushed prasugrel (Effient) to patients with ST-segment elevation myocardial infarction (STEMI) en route to a planned primary percutaneous coronary intervention (PCI) does not improve reperfusion rates, results of the COMPARE CRUSH trial show.
Patients assigned to prasugrel as crushed or integral tablets had similar rates of the study’s co-primary endpoints of thrombolysis in myocardial infarction (TIMI) 3 flow in the infarct-related artery at first angiography (31% vs. 32.7%; P = .64) and complete ST-segment resolution 1 hour post PCI (59.9% vs. 57.3%; P = .55).
“These findings hold in spite of the fact that crushed tablets of prasugrel led to more potent platelet inhibition compared with integral tablets,” said study author Georgios Vlachojannis, MD, PhD, University Medical Center Utrecht, the Netherlands.
“Whether faster and more potent antiplatelet therapy can improve coronary reperfusion in contemporary STEMI treatment regimen warrants further investigation.”
The results were reported in a late-breaking clinical science session at the Transcatheter Cardiovascular Therapeutics virtual annual meeting and published simultaneously in the journal Circulation. The meeting was sponsored by the Cardiovascular Research Foundation.
Fibrinolytics and glycoprotein IIb/IIIa inhibitors have demonstrated improved coronary reperfusion and outcomes when given pre hospital. Prior studies have also shown that early administration of a crushed P2Y12 inhibitor increases bioavailability and speeds platelet inhibition in STEMI patients, Dr. Vlachojannis noted.
However, the large randomized ATLANTIC trial, which compared prehospital to cath lab administration of crushed or integral ticagrelor (Brilinta), also found no difference in either TIMI flow in the infarct-related artery or ST-segment resolution.
Between November 2017 and March 2020, the investigator-initiated COMPARE CRUSH trial randomly allocated 727 STEMI patients (mean age, 62 years; 23% female) undergoing primary PCI to receive in the ambulance a 60-mg loading dose of prasugrel as either crushed or integral tablets.
The median time from onset of symptoms to first medical contact was 59 minutes, from first medical contact to study treatment 22 minutes, and from study treatment to primary PCI 57 minutes. These times did not differ between groups.
Platelet reactivity at the beginning of coronary angiography was significantly lower in the crushed group than in the integral group (P2Y12 reactivity units 192 vs. 227; P < .01). This resulted in significantly fewer patients in the crushed group with high platelet reactivity, defined as P2Y12 reactivity units >208, prior to the start of PCI (43.3% vs. 62.6%; P < .01).
There was no difference between the crushed and integral groups in the primary safety endpoint of TIMI major and BARC type 3 or higher bleeding within 48 hours after study treatment (0.4% vs 0.7%).
Death, MI, stroke, and urgent revascularization rates were also similar between groups during index hospitalization and at 30 days. Definite stent thrombosis occurred in one patient in the crushed group and two patients in the integral group.
In an exploratory analysis, the co-primary endpoint results were consistent across multiple subgroups, although there was a trend toward greater benefit on TIMI 3 flow in the crushed tablet group in patients older than age 75 years (P for interaction = .04), presenting with anterior infarction (P for interaction = .03), or with a history of prior PCI (P for interaction < .01).
“However, these results should be regarded as hypothesis-generating,” the authors wrote. “Opioids use in the ambulance was remarkably low in our study compared with the ATLANTIC trial, which might explain that we did not observe any significant interaction.”
Notably, morphine was used in half the ATLANTIC patients and was thought to have possibly delayed the absorption of ticagrelor.
During discussion following the presentation, Sunil V. Rao, MD, Duke University Medical Center, Durham, N.C., asked: “Based on what you found, which is really no clinical advantage but no safety issue either, are you having your patients with ST-segment MI administering crushed prasugrel now?”
Dr. Vlachojannis said they didn’t see any clinical impact but reiterated that high platelet reactivity was reduced by one-third. “If this now translates into a safer primary PCI procedure, we can’t say. The study wasn’t powered for this kind of endpoint. Is this enough to give you a recommendation, Sunil, I’m not sure.”
“What we know with COMPARE CRUSH, and this is important, is that we tried to give the medication as soon as possible and tried to give this medication in a formulation which has the most favorable pharmacodynamics profile, and we still see it’s not doing the job,” he added.
Fellow panelist Philippe Gabriel Steg, MD, Imperial College London, questioned whether treatment time may play a role in teasing out the relatively modest differences that platelet reactivity may have on clinical outcomes.
Dr. Vlachojannis said the time from symptom onset to first medical contact was very fast and similar to that in the ATLANTIC trial. “The short time intervals have certainly influenced the outcomes.”
Panelist Marco Valgimigli, MD, PhD, University Hospital Bern, Switzerland, followed up on the morphine issue, asking whether the investigators tested for an interaction between morphine or opioid use and platelet reactivity at the time of PCI.
“We haven’t looked into this but you probably have the ON-TIME 3 data in your mind when you’re asking this, where crushed ticagrelor given in the ambulance didn’t influence platelet reactivity at the time point of PCI,” Dr. Vlachojannis said. “We are going to look further into the data and certainly the platelet reactivity analysis is going to be very interesting in this data set.”
The study was an investigator-initiated trial sponsored by Maasstad Cardiovascular Research B.V. with unrestricted grants from Shanghai MicroPort Medical and Daiichi Sankyo. Dr. Vlachojannis declared receiving consulting fees from AstraZeneca, and research grants from Daiichi Sankyo and Shanghai MicroPort.
A version of this article originally appeared on Medscape.com.
Giving crushed prasugrel (Effient) to patients with ST-segment elevation myocardial infarction (STEMI) en route to a planned primary percutaneous coronary intervention (PCI) does not improve reperfusion rates, results of the COMPARE CRUSH trial show.
Patients assigned to prasugrel as crushed or integral tablets had similar rates of the study’s co-primary endpoints of thrombolysis in myocardial infarction (TIMI) 3 flow in the infarct-related artery at first angiography (31% vs. 32.7%; P = .64) and complete ST-segment resolution 1 hour post PCI (59.9% vs. 57.3%; P = .55).
“These findings hold in spite of the fact that crushed tablets of prasugrel led to more potent platelet inhibition compared with integral tablets,” said study author Georgios Vlachojannis, MD, PhD, University Medical Center Utrecht, the Netherlands.
“Whether faster and more potent antiplatelet therapy can improve coronary reperfusion in contemporary STEMI treatment regimen warrants further investigation.”
The results were reported in a late-breaking clinical science session at the Transcatheter Cardiovascular Therapeutics virtual annual meeting and published simultaneously in the journal Circulation. The meeting was sponsored by the Cardiovascular Research Foundation.
Fibrinolytics and glycoprotein IIb/IIIa inhibitors have demonstrated improved coronary reperfusion and outcomes when given pre hospital. Prior studies have also shown that early administration of a crushed P2Y12 inhibitor increases bioavailability and speeds platelet inhibition in STEMI patients, Dr. Vlachojannis noted.
However, the large randomized ATLANTIC trial, which compared prehospital to cath lab administration of crushed or integral ticagrelor (Brilinta), also found no difference in either TIMI flow in the infarct-related artery or ST-segment resolution.
Between November 2017 and March 2020, the investigator-initiated COMPARE CRUSH trial randomly allocated 727 STEMI patients (mean age, 62 years; 23% female) undergoing primary PCI to receive in the ambulance a 60-mg loading dose of prasugrel as either crushed or integral tablets.
The median time from onset of symptoms to first medical contact was 59 minutes, from first medical contact to study treatment 22 minutes, and from study treatment to primary PCI 57 minutes. These times did not differ between groups.
Platelet reactivity at the beginning of coronary angiography was significantly lower in the crushed group than in the integral group (P2Y12 reactivity units 192 vs. 227; P < .01). This resulted in significantly fewer patients in the crushed group with high platelet reactivity, defined as P2Y12 reactivity units >208, prior to the start of PCI (43.3% vs. 62.6%; P < .01).
There was no difference between the crushed and integral groups in the primary safety endpoint of TIMI major and BARC type 3 or higher bleeding within 48 hours after study treatment (0.4% vs 0.7%).
Death, MI, stroke, and urgent revascularization rates were also similar between groups during index hospitalization and at 30 days. Definite stent thrombosis occurred in one patient in the crushed group and two patients in the integral group.
In an exploratory analysis, the co-primary endpoint results were consistent across multiple subgroups, although there was a trend toward greater benefit on TIMI 3 flow in the crushed tablet group in patients older than age 75 years (P for interaction = .04), presenting with anterior infarction (P for interaction = .03), or with a history of prior PCI (P for interaction < .01).
“However, these results should be regarded as hypothesis-generating,” the authors wrote. “Opioids use in the ambulance was remarkably low in our study compared with the ATLANTIC trial, which might explain that we did not observe any significant interaction.”
Notably, morphine was used in half the ATLANTIC patients and was thought to have possibly delayed the absorption of ticagrelor.
During discussion following the presentation, Sunil V. Rao, MD, Duke University Medical Center, Durham, N.C., asked: “Based on what you found, which is really no clinical advantage but no safety issue either, are you having your patients with ST-segment MI administering crushed prasugrel now?”
Dr. Vlachojannis said they didn’t see any clinical impact but reiterated that high platelet reactivity was reduced by one-third. “If this now translates into a safer primary PCI procedure, we can’t say. The study wasn’t powered for this kind of endpoint. Is this enough to give you a recommendation, Sunil, I’m not sure.”
“What we know with COMPARE CRUSH, and this is important, is that we tried to give the medication as soon as possible and tried to give this medication in a formulation which has the most favorable pharmacodynamics profile, and we still see it’s not doing the job,” he added.
Fellow panelist Philippe Gabriel Steg, MD, Imperial College London, questioned whether treatment time may play a role in teasing out the relatively modest differences that platelet reactivity may have on clinical outcomes.
Dr. Vlachojannis said the time from symptom onset to first medical contact was very fast and similar to that in the ATLANTIC trial. “The short time intervals have certainly influenced the outcomes.”
Panelist Marco Valgimigli, MD, PhD, University Hospital Bern, Switzerland, followed up on the morphine issue, asking whether the investigators tested for an interaction between morphine or opioid use and platelet reactivity at the time of PCI.
“We haven’t looked into this but you probably have the ON-TIME 3 data in your mind when you’re asking this, where crushed ticagrelor given in the ambulance didn’t influence platelet reactivity at the time point of PCI,” Dr. Vlachojannis said. “We are going to look further into the data and certainly the platelet reactivity analysis is going to be very interesting in this data set.”
The study was an investigator-initiated trial sponsored by Maasstad Cardiovascular Research B.V. with unrestricted grants from Shanghai MicroPort Medical and Daiichi Sankyo. Dr. Vlachojannis declared receiving consulting fees from AstraZeneca, and research grants from Daiichi Sankyo and Shanghai MicroPort.
A version of this article originally appeared on Medscape.com.
Giving crushed prasugrel (Effient) to patients with ST-segment elevation myocardial infarction (STEMI) en route to a planned primary percutaneous coronary intervention (PCI) does not improve reperfusion rates, results of the COMPARE CRUSH trial show.
Patients assigned to prasugrel as crushed or integral tablets had similar rates of the study’s co-primary endpoints of thrombolysis in myocardial infarction (TIMI) 3 flow in the infarct-related artery at first angiography (31% vs. 32.7%; P = .64) and complete ST-segment resolution 1 hour post PCI (59.9% vs. 57.3%; P = .55).
“These findings hold in spite of the fact that crushed tablets of prasugrel led to more potent platelet inhibition compared with integral tablets,” said study author Georgios Vlachojannis, MD, PhD, University Medical Center Utrecht, the Netherlands.
“Whether faster and more potent antiplatelet therapy can improve coronary reperfusion in contemporary STEMI treatment regimen warrants further investigation.”
The results were reported in a late-breaking clinical science session at the Transcatheter Cardiovascular Therapeutics virtual annual meeting and published simultaneously in the journal Circulation. The meeting was sponsored by the Cardiovascular Research Foundation.
Fibrinolytics and glycoprotein IIb/IIIa inhibitors have demonstrated improved coronary reperfusion and outcomes when given pre hospital. Prior studies have also shown that early administration of a crushed P2Y12 inhibitor increases bioavailability and speeds platelet inhibition in STEMI patients, Dr. Vlachojannis noted.
However, the large randomized ATLANTIC trial, which compared prehospital to cath lab administration of crushed or integral ticagrelor (Brilinta), also found no difference in either TIMI flow in the infarct-related artery or ST-segment resolution.
Between November 2017 and March 2020, the investigator-initiated COMPARE CRUSH trial randomly allocated 727 STEMI patients (mean age, 62 years; 23% female) undergoing primary PCI to receive in the ambulance a 60-mg loading dose of prasugrel as either crushed or integral tablets.
The median time from onset of symptoms to first medical contact was 59 minutes, from first medical contact to study treatment 22 minutes, and from study treatment to primary PCI 57 minutes. These times did not differ between groups.
Platelet reactivity at the beginning of coronary angiography was significantly lower in the crushed group than in the integral group (P2Y12 reactivity units 192 vs. 227; P < .01). This resulted in significantly fewer patients in the crushed group with high platelet reactivity, defined as P2Y12 reactivity units >208, prior to the start of PCI (43.3% vs. 62.6%; P < .01).
There was no difference between the crushed and integral groups in the primary safety endpoint of TIMI major and BARC type 3 or higher bleeding within 48 hours after study treatment (0.4% vs 0.7%).
Death, MI, stroke, and urgent revascularization rates were also similar between groups during index hospitalization and at 30 days. Definite stent thrombosis occurred in one patient in the crushed group and two patients in the integral group.
In an exploratory analysis, the co-primary endpoint results were consistent across multiple subgroups, although there was a trend toward greater benefit on TIMI 3 flow in the crushed tablet group in patients older than age 75 years (P for interaction = .04), presenting with anterior infarction (P for interaction = .03), or with a history of prior PCI (P for interaction < .01).
“However, these results should be regarded as hypothesis-generating,” the authors wrote. “Opioids use in the ambulance was remarkably low in our study compared with the ATLANTIC trial, which might explain that we did not observe any significant interaction.”
Notably, morphine was used in half the ATLANTIC patients and was thought to have possibly delayed the absorption of ticagrelor.
During discussion following the presentation, Sunil V. Rao, MD, Duke University Medical Center, Durham, N.C., asked: “Based on what you found, which is really no clinical advantage but no safety issue either, are you having your patients with ST-segment MI administering crushed prasugrel now?”
Dr. Vlachojannis said they didn’t see any clinical impact but reiterated that high platelet reactivity was reduced by one-third. “If this now translates into a safer primary PCI procedure, we can’t say. The study wasn’t powered for this kind of endpoint. Is this enough to give you a recommendation, Sunil, I’m not sure.”
“What we know with COMPARE CRUSH, and this is important, is that we tried to give the medication as soon as possible and tried to give this medication in a formulation which has the most favorable pharmacodynamics profile, and we still see it’s not doing the job,” he added.
Fellow panelist Philippe Gabriel Steg, MD, Imperial College London, questioned whether treatment time may play a role in teasing out the relatively modest differences that platelet reactivity may have on clinical outcomes.
Dr. Vlachojannis said the time from symptom onset to first medical contact was very fast and similar to that in the ATLANTIC trial. “The short time intervals have certainly influenced the outcomes.”
Panelist Marco Valgimigli, MD, PhD, University Hospital Bern, Switzerland, followed up on the morphine issue, asking whether the investigators tested for an interaction between morphine or opioid use and platelet reactivity at the time of PCI.
“We haven’t looked into this but you probably have the ON-TIME 3 data in your mind when you’re asking this, where crushed ticagrelor given in the ambulance didn’t influence platelet reactivity at the time point of PCI,” Dr. Vlachojannis said. “We are going to look further into the data and certainly the platelet reactivity analysis is going to be very interesting in this data set.”
The study was an investigator-initiated trial sponsored by Maasstad Cardiovascular Research B.V. with unrestricted grants from Shanghai MicroPort Medical and Daiichi Sankyo. Dr. Vlachojannis declared receiving consulting fees from AstraZeneca, and research grants from Daiichi Sankyo and Shanghai MicroPort.
A version of this article originally appeared on Medscape.com.
Hand eczema: Pan-JAK inhibitor delgocitinib shows dose-dependent response in phase 2b trial
a new international phase 2b research suggests.
An investigational pan–Janus kinase inhibitor that blocks all four members of the JAK family, twice-daily delgocitinib doses of 8 mg/g and 20 mg/g demonstrated the highest efficacy in adults with mild to severe chronic hand eczema. By week 16, nearly 40% of patients receiving either dose were clear or almost clear of symptoms.
“By mode of action, we think delgocitinib is more selective in the way of acting,” said lead investigator Margitta Worm, MD, PhD, of the department of dermatology, venereology, and allergology at Charité University Hospital in Berlin, during a presentation of the results at the virtual annual congress of the European Academy of Dermatology and Venereology.
“We do know that JAKs play an important role in chronic inflammation and interfering with the JAK pathway can have anti-inflammatory effects,” Dr. Worm said in an interview. “Whenever it’s possible to use a molecule topically or locally, it’s advantageous for patients because it’s only acting where you apply it and there are no systemic side effects.”
Defined as lasting more than 3 months or relapsing twice or more within a year, chronic hand eczema is a particularly problematic form of atopic dermatitis because “we need our hands every day for almost every activity, so having eczema on your hands has a huge impact on quality of life,” Dr. Worm said.
Many people whose hands are integral to their occupations also have trouble working because of the disorder, she explained. But current topical treatments are limited to emollients, corticosteroids, and calcineurin inhibitors.
“Topical corticosteroids are efficacious, but can cause skin atrophy,” she said. “Their long-term side-effect profile limits their use.”
The number of patients in each treatment group was too small to focus on different subtypes of chronic hand eczema, “but this is something that will probably be looked at in the future,” Dr. Worm said. “At the moment it’s nice to see a dose-dependent clinical efficacy and good tolerability, and now we have to wait for phase 3 data in the future.”
Dr. Worm and colleagues aimed to establish the dose-response relationship of twice-daily applications of delgocitinib cream in doses of 1, 3, 8, and 20 mg/g and a delgocitinib cream vehicle for 16 weeks. The 258 participants (61% women; average age, 46 years) were randomly assigned in equal groups to each dose of delgocitinib cream or the vehicle cream twice daily at centers in Denmark, Germany, and the United States.
The primary endpoint for the double-blind, 26-center trial was the proportion of patients who achieved an Investigator’s Global Assessment score of 0 (“clear”) or 1 (“almost clear”), with a 2-point or higher improvement from baseline over the study period. A key secondary endpoint was a change in the Hand Eczema Severity Index (HECSI) from baseline to week 16.
At week 16, a statistically significant dose response was established for both primary and secondary endpoints (P < .025). More patients in the delgocitinib 8-mg/g and 20-mg/g groups met the primary endpoint (36.5% and 37.7%, respectively) than patients in the 1-mg/g and 3-mg/g groups (21.2% and 7.8%, respectively) and vehicle group (8%, P = .0004).
This primary skin clearance effect at week 16 was demonstrated from week 4 in the 8-mg/g group and week 6 in the 20-mg/g group. But all active doses achieved a statistically significant greater jump in HECSI from baseline to week 16 than the vehicle cream (P < .05).
“The strength of the trial is that there were different concentrations of the substance used,” Dr. Worm said. “When you look to the results, you can demonstrate a dose-dependent clinical efficacy. This is of great value to really compare the efficacy of single doses.”
Most adverse events reported were not considered treatment related and were mild or moderate. The most frequently reported side effects were nasopharyngitis, eczema, and headache.
Commenting on the results, Asli Bilgic, MD, from Akdeniz University in Antalya, Turkey, who was not involved with the study, said that phase 3 studies of delgocitinib should probe further into the effects of the 8-mg/g dosage in this patient group since it appears to show similar efficacy and safety to 20 mg/g.
It’s important for research to focus on hand eczema “because it’s a very common disease, and treatment options are really sparse,” Dr. Bilgic said in an interview.
“Especially in the COVID era, many health care professionals, along with cleaning, catering, and mechanical jobs” are essential workers affected by the condition, she said. “It affects people’s self-esteem and their ability to do their job.”
The study was funded by LEO Pharma. Dr. Worm received lecture honoraria from LEO Pharma. Dr. Bilgic disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
a new international phase 2b research suggests.
An investigational pan–Janus kinase inhibitor that blocks all four members of the JAK family, twice-daily delgocitinib doses of 8 mg/g and 20 mg/g demonstrated the highest efficacy in adults with mild to severe chronic hand eczema. By week 16, nearly 40% of patients receiving either dose were clear or almost clear of symptoms.
“By mode of action, we think delgocitinib is more selective in the way of acting,” said lead investigator Margitta Worm, MD, PhD, of the department of dermatology, venereology, and allergology at Charité University Hospital in Berlin, during a presentation of the results at the virtual annual congress of the European Academy of Dermatology and Venereology.
“We do know that JAKs play an important role in chronic inflammation and interfering with the JAK pathway can have anti-inflammatory effects,” Dr. Worm said in an interview. “Whenever it’s possible to use a molecule topically or locally, it’s advantageous for patients because it’s only acting where you apply it and there are no systemic side effects.”
Defined as lasting more than 3 months or relapsing twice or more within a year, chronic hand eczema is a particularly problematic form of atopic dermatitis because “we need our hands every day for almost every activity, so having eczema on your hands has a huge impact on quality of life,” Dr. Worm said.
Many people whose hands are integral to their occupations also have trouble working because of the disorder, she explained. But current topical treatments are limited to emollients, corticosteroids, and calcineurin inhibitors.
“Topical corticosteroids are efficacious, but can cause skin atrophy,” she said. “Their long-term side-effect profile limits their use.”
The number of patients in each treatment group was too small to focus on different subtypes of chronic hand eczema, “but this is something that will probably be looked at in the future,” Dr. Worm said. “At the moment it’s nice to see a dose-dependent clinical efficacy and good tolerability, and now we have to wait for phase 3 data in the future.”
Dr. Worm and colleagues aimed to establish the dose-response relationship of twice-daily applications of delgocitinib cream in doses of 1, 3, 8, and 20 mg/g and a delgocitinib cream vehicle for 16 weeks. The 258 participants (61% women; average age, 46 years) were randomly assigned in equal groups to each dose of delgocitinib cream or the vehicle cream twice daily at centers in Denmark, Germany, and the United States.
The primary endpoint for the double-blind, 26-center trial was the proportion of patients who achieved an Investigator’s Global Assessment score of 0 (“clear”) or 1 (“almost clear”), with a 2-point or higher improvement from baseline over the study period. A key secondary endpoint was a change in the Hand Eczema Severity Index (HECSI) from baseline to week 16.
At week 16, a statistically significant dose response was established for both primary and secondary endpoints (P < .025). More patients in the delgocitinib 8-mg/g and 20-mg/g groups met the primary endpoint (36.5% and 37.7%, respectively) than patients in the 1-mg/g and 3-mg/g groups (21.2% and 7.8%, respectively) and vehicle group (8%, P = .0004).
This primary skin clearance effect at week 16 was demonstrated from week 4 in the 8-mg/g group and week 6 in the 20-mg/g group. But all active doses achieved a statistically significant greater jump in HECSI from baseline to week 16 than the vehicle cream (P < .05).
“The strength of the trial is that there were different concentrations of the substance used,” Dr. Worm said. “When you look to the results, you can demonstrate a dose-dependent clinical efficacy. This is of great value to really compare the efficacy of single doses.”
Most adverse events reported were not considered treatment related and were mild or moderate. The most frequently reported side effects were nasopharyngitis, eczema, and headache.
Commenting on the results, Asli Bilgic, MD, from Akdeniz University in Antalya, Turkey, who was not involved with the study, said that phase 3 studies of delgocitinib should probe further into the effects of the 8-mg/g dosage in this patient group since it appears to show similar efficacy and safety to 20 mg/g.
It’s important for research to focus on hand eczema “because it’s a very common disease, and treatment options are really sparse,” Dr. Bilgic said in an interview.
“Especially in the COVID era, many health care professionals, along with cleaning, catering, and mechanical jobs” are essential workers affected by the condition, she said. “It affects people’s self-esteem and their ability to do their job.”
The study was funded by LEO Pharma. Dr. Worm received lecture honoraria from LEO Pharma. Dr. Bilgic disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
a new international phase 2b research suggests.
An investigational pan–Janus kinase inhibitor that blocks all four members of the JAK family, twice-daily delgocitinib doses of 8 mg/g and 20 mg/g demonstrated the highest efficacy in adults with mild to severe chronic hand eczema. By week 16, nearly 40% of patients receiving either dose were clear or almost clear of symptoms.
“By mode of action, we think delgocitinib is more selective in the way of acting,” said lead investigator Margitta Worm, MD, PhD, of the department of dermatology, venereology, and allergology at Charité University Hospital in Berlin, during a presentation of the results at the virtual annual congress of the European Academy of Dermatology and Venereology.
“We do know that JAKs play an important role in chronic inflammation and interfering with the JAK pathway can have anti-inflammatory effects,” Dr. Worm said in an interview. “Whenever it’s possible to use a molecule topically or locally, it’s advantageous for patients because it’s only acting where you apply it and there are no systemic side effects.”
Defined as lasting more than 3 months or relapsing twice or more within a year, chronic hand eczema is a particularly problematic form of atopic dermatitis because “we need our hands every day for almost every activity, so having eczema on your hands has a huge impact on quality of life,” Dr. Worm said.
Many people whose hands are integral to their occupations also have trouble working because of the disorder, she explained. But current topical treatments are limited to emollients, corticosteroids, and calcineurin inhibitors.
“Topical corticosteroids are efficacious, but can cause skin atrophy,” she said. “Their long-term side-effect profile limits their use.”
The number of patients in each treatment group was too small to focus on different subtypes of chronic hand eczema, “but this is something that will probably be looked at in the future,” Dr. Worm said. “At the moment it’s nice to see a dose-dependent clinical efficacy and good tolerability, and now we have to wait for phase 3 data in the future.”
Dr. Worm and colleagues aimed to establish the dose-response relationship of twice-daily applications of delgocitinib cream in doses of 1, 3, 8, and 20 mg/g and a delgocitinib cream vehicle for 16 weeks. The 258 participants (61% women; average age, 46 years) were randomly assigned in equal groups to each dose of delgocitinib cream or the vehicle cream twice daily at centers in Denmark, Germany, and the United States.
The primary endpoint for the double-blind, 26-center trial was the proportion of patients who achieved an Investigator’s Global Assessment score of 0 (“clear”) or 1 (“almost clear”), with a 2-point or higher improvement from baseline over the study period. A key secondary endpoint was a change in the Hand Eczema Severity Index (HECSI) from baseline to week 16.
At week 16, a statistically significant dose response was established for both primary and secondary endpoints (P < .025). More patients in the delgocitinib 8-mg/g and 20-mg/g groups met the primary endpoint (36.5% and 37.7%, respectively) than patients in the 1-mg/g and 3-mg/g groups (21.2% and 7.8%, respectively) and vehicle group (8%, P = .0004).
This primary skin clearance effect at week 16 was demonstrated from week 4 in the 8-mg/g group and week 6 in the 20-mg/g group. But all active doses achieved a statistically significant greater jump in HECSI from baseline to week 16 than the vehicle cream (P < .05).
“The strength of the trial is that there were different concentrations of the substance used,” Dr. Worm said. “When you look to the results, you can demonstrate a dose-dependent clinical efficacy. This is of great value to really compare the efficacy of single doses.”
Most adverse events reported were not considered treatment related and were mild or moderate. The most frequently reported side effects were nasopharyngitis, eczema, and headache.
Commenting on the results, Asli Bilgic, MD, from Akdeniz University in Antalya, Turkey, who was not involved with the study, said that phase 3 studies of delgocitinib should probe further into the effects of the 8-mg/g dosage in this patient group since it appears to show similar efficacy and safety to 20 mg/g.
It’s important for research to focus on hand eczema “because it’s a very common disease, and treatment options are really sparse,” Dr. Bilgic said in an interview.
“Especially in the COVID era, many health care professionals, along with cleaning, catering, and mechanical jobs” are essential workers affected by the condition, she said. “It affects people’s self-esteem and their ability to do their job.”
The study was funded by LEO Pharma. Dr. Worm received lecture honoraria from LEO Pharma. Dr. Bilgic disclosed no relevant financial relationships.
A version of this article originally appeared on Medscape.com.
FROM THE EADV CONGRESS
Physician burnout costly to organizations and U.S. health system
Background: Occupational burnout is more prevalent among physicians than among the general population, and physician burnout is associated with several negative clinical outcomes. However, little is known about the economic cost of this widespread issue.
Study design: Cost-consequence analysis using a novel mathematical model.
Setting: Simulated population of U.S. physicians.
Synopsis: Researchers conducted a cost-consequence analysis using a mathematical model designed to determine the financial impact of burnout – or the difference in observed cost and the theoretical cost if physicians did not experience burnout. The model used a hypothetical physician population based on a 2013 profile of U.S. physicians, a 2014 survey of physicians that assessed burnout, and preexisting literature on burnout to generate the input data for their model. The investigators focused on two outcomes: turnover and reduction in clinical hours. They found that approximately $4.6 billion per year is lost in direct cost secondary to physician burnout, with the greatest proportion coming from physician turnover. The figure ranged from $2.6 billion to $6.3 billion in multivariate sensitivity analysis. For an organization, the cost of burnout is about $7,600 per physician per year, with a range of $4,100 to $10,200. Though statistical modeling can be imprecise, and the input data were imperfect, the study was the first to examine the systemwide cost of physician burnout in the United States.
Bottom line: Along with the negative effects on physician and patient well-being, physician burnout is financially costly to the U.S. health care system and to individual organizations. Programs to reduce burnout could be both ethically and economically advantageous.
Citation: Han S et al. Estimating the attributable cost of physician burnout in the United States. Ann Intern Med. 2019;170(11):784-90.
Dr. Suojanen is a hospitalist at Vanderbilt University Medical Center, Nashville, Tenn.
Background: Occupational burnout is more prevalent among physicians than among the general population, and physician burnout is associated with several negative clinical outcomes. However, little is known about the economic cost of this widespread issue.
Study design: Cost-consequence analysis using a novel mathematical model.
Setting: Simulated population of U.S. physicians.
Synopsis: Researchers conducted a cost-consequence analysis using a mathematical model designed to determine the financial impact of burnout – or the difference in observed cost and the theoretical cost if physicians did not experience burnout. The model used a hypothetical physician population based on a 2013 profile of U.S. physicians, a 2014 survey of physicians that assessed burnout, and preexisting literature on burnout to generate the input data for their model. The investigators focused on two outcomes: turnover and reduction in clinical hours. They found that approximately $4.6 billion per year is lost in direct cost secondary to physician burnout, with the greatest proportion coming from physician turnover. The figure ranged from $2.6 billion to $6.3 billion in multivariate sensitivity analysis. For an organization, the cost of burnout is about $7,600 per physician per year, with a range of $4,100 to $10,200. Though statistical modeling can be imprecise, and the input data were imperfect, the study was the first to examine the systemwide cost of physician burnout in the United States.
Bottom line: Along with the negative effects on physician and patient well-being, physician burnout is financially costly to the U.S. health care system and to individual organizations. Programs to reduce burnout could be both ethically and economically advantageous.
Citation: Han S et al. Estimating the attributable cost of physician burnout in the United States. Ann Intern Med. 2019;170(11):784-90.
Dr. Suojanen is a hospitalist at Vanderbilt University Medical Center, Nashville, Tenn.
Background: Occupational burnout is more prevalent among physicians than among the general population, and physician burnout is associated with several negative clinical outcomes. However, little is known about the economic cost of this widespread issue.
Study design: Cost-consequence analysis using a novel mathematical model.
Setting: Simulated population of U.S. physicians.
Synopsis: Researchers conducted a cost-consequence analysis using a mathematical model designed to determine the financial impact of burnout – or the difference in observed cost and the theoretical cost if physicians did not experience burnout. The model used a hypothetical physician population based on a 2013 profile of U.S. physicians, a 2014 survey of physicians that assessed burnout, and preexisting literature on burnout to generate the input data for their model. The investigators focused on two outcomes: turnover and reduction in clinical hours. They found that approximately $4.6 billion per year is lost in direct cost secondary to physician burnout, with the greatest proportion coming from physician turnover. The figure ranged from $2.6 billion to $6.3 billion in multivariate sensitivity analysis. For an organization, the cost of burnout is about $7,600 per physician per year, with a range of $4,100 to $10,200. Though statistical modeling can be imprecise, and the input data were imperfect, the study was the first to examine the systemwide cost of physician burnout in the United States.
Bottom line: Along with the negative effects on physician and patient well-being, physician burnout is financially costly to the U.S. health care system and to individual organizations. Programs to reduce burnout could be both ethically and economically advantageous.
Citation: Han S et al. Estimating the attributable cost of physician burnout in the United States. Ann Intern Med. 2019;170(11):784-90.
Dr. Suojanen is a hospitalist at Vanderbilt University Medical Center, Nashville, Tenn.
Med student’s cardiac crisis a COVID-era medical mystery
Within minutes of her arrival at Community North Hospital in Indianapolis, Ramya Yeleti’s vital signs plummeted; her pulse was at 45 beats per minute and her ejection fraction was hovering near 10%. “I definitely thought there was a chance I would close my eyes and never open them again, but I only had a few seconds to process that,” she recalled. Then everything went black. Ramya fell unconscious as shock pads were positioned and a swarm of clinicians prepared to insert an Impella heart pump through a catheter into her aorta.
The third-year medical student and aspiring psychiatrist had been doing in-person neurology rotations in July when she began to experience fever and uncontrolled vomiting. Her initial thought was that she must have caught the flu from a patient.
After all, Ramya, along with her father Ram Yeleti, MD, mother Indira, and twin sister Divya, had all weathered COVID-19 in previous months and later tested positive for SARS-CoV-2 antibodies. The only family member who had been spared was her younger brother Rohith.
Indira suffered a severe case, requiring ICU care for 2 days but no ventilator; the others experienced mostly mild symptoms. Ramya — who was studying for her third-year board exams after classes at Marian University College of Osteopathic Medicine in Indianapolis went virtual in March — was left with lingering fatigue; however, her cough and muscle aches abated and her sense of taste and smell returned. When she started rotations, she thought her life was getting back to normal.
Ramya’s flu symptoms did not improve. A university-mandated rapid COVID test came back negative, but 2 more days of vomiting started to worry both her and her father, who is a cardiologist and chief physician executive at Community Health Network in Indianapolis. After Ramya felt some chest pain, she asked her father to listen to her heart. All sounded normal, and Ram prescribed ondansetron for her nausea.
But the antiemetic didn’t work, and by the next morning both father and daughter were convinced that they needed to head to the emergency department.
“I wanted to double-check if I was missing something about her being dehydrated,” Ram told Medscape Medical News. “Several things can cause protracted nausea, like hepatitis, appendicitis, or another infection. I feel terribly guilty I didn’t realize she had a heart condition.”
A surprising turn for the worst
Ramya’s subtle symptoms quickly gave way to the dramatic cardiac crisis that unfolded just after her arrival at Community North. “Her EKG looked absolutely horrendous, like a 75-year-old having a heart attack,” Ram said.
As a cardiologist, he knew his daughter’s situation was growing dire when he heard physicians shouting that the Impella wasn’t working and she needed extracorporeal membrane oxygenation (ECMO).
“At that point, I didn’t think she’d survive,” her father recalled. “We had 10 physicians in the room who worked on her for 5 hours to get her stabilized.”
“It was especially traumatic because, obviously, I knew exactly what was happening,” he added. “You can’t sugarcoat anything.”
After being connected to the heart–lung equipment, Ramya was transferred to IU Health Methodist Hospital, also in Indianapolis, where she was tested again for COVID-19. Unlike the rapid test administered just days earlier, the PCR assay came back positive.
“I knew she had acute myocarditis, but coronavirus never crossed my mind,” said Ram.
“As we were dealing with her heart, we were also dealing with this challenge: she was coming back positive for COVID-19 again,” said Roopa Rao, MD, the heart failure transplant cardiologist at IU Health who treated Ramya.
“We weren’t sure whether we were dealing with an active infection or dead virus” from her previous infection, Rao said, “so we started treating her like she had active COVID-19 and gave her remdesivir, convalescent plasma, and steroids, which was the protocol in our hospital.”
A biopsy of Ramya’s heart tissue, along with blood tests, indicated a past parvovirus infection. It’s possible that Ramya’s previous coronavirus infection made her susceptible to heart damage from a newer parvovirus infection, said Rao. Either virus, or both together, could have been responsible for the calamity.
Although it was unheard of during Ramya’s cardiac crisis in early August, evolving evidence now raises the possibility that she is one of a handful of people in the world to be reinfected with SARS-CoV-2. Also emerging are cases of COVID-related myocarditis and other extreme heart complications, particularly in young people.
“At the time, it wasn’t really clear if people could have another infection so quickly,” Rao told Medscape Medical News. “It is possible she is one of these rare individuals to have COVID-19 twice. I’m hoping at some point we will have some clarity.”
“I would favor a coinfection as probably the triggering factor for her sickness,” she said. “It may take some time, but like any other disease — and it doesn’t look like COVID will go away magically — I hope we’ll have some answers down the road.”
Another wrinkle
The next 48 hours brought astonishing news: Ramya’s heart function had rebounded to nearly normal, and her ejection fraction increased to about 45%. Heart transplantation wouldn’t be necessary, although Rao stood poised to follow through if ECMO only sustained, rather than improved, Ramya’s prognosis.
“Ramya was so sick that if she didn’t recover, the only option would be a heart transplant,” said Rao. “But we wanted to do everything to keep that heart.”
After steroid and COVID treatment, Ramya’s heart started to come back. “It didn’t make sense to me,” said Rao. “I don’t know what helped. If we hadn’t done ECMO, her heart probably wouldn’t have recovered, so I would say we have to support these patients and give them time for the heart to recover, even to the point of ECMO.”
Despite the good news, Ramya’s survival still hung in the balance. When she was disconnected from ECMO, clinicians discovered that the Impella device had caused a rare complication, damaging her mitral valve. The valve could be repaired surgically, but both Rao and Ram felt great trepidation at the prospect of cardiopulmonary bypass during the open-heart procedure.
“They would need to stop her heart and restart it, and I was concerned it would not restart,” Ram explained. “I didn’t like the idea of open-heart surgery, but my biggest fear was she was not going to survive it because of a really fresh, sick heart.”
The cardiologists’ fears did, in fact, come to pass: it took an hour to coax Ramya’s heart back at the end of surgery. But, just as the surgeon was preparing to reconnect Ramya to ECMO in desperation, “her heart recovered again,” Rao reported.
“Some things you never forget in life,” she said. “I can’t describe how everyone in the OR felt, all taking care of her. I told Ramya, ‘you are a fighter’.”
New strength
Six days would pass before Ramya woke up and learned of the astounding series of events that saved her. She knew “something was really wrong” because of the incision at the center of her chest, but learning she’d been on ECMO and the heart transplant list drove home how close to death she’d actually come.
“Most people don’t get off ECMO; they die on it,” she said. “And the chances of dying on the heart transplant list are very high. It was very strange to me that this was my story all of a sudden, when a week and a half earlier I was on rotation.”
Ongoing physical therapy over the past 3 months has transformed Ramya from a state of profound physical weakness to a place of relative strength. The now-fourth-year med student is turning 26 in November and is hungry to restart in-person rotations. Her downtime has been filled in part with researching myocarditis and collaborating with Rao on her own case study for journal publication.
But the mental trauma from her experience has girded her in ways she knows will make her stronger personally and professionally in the years ahead.
“It’s still very hard. I’m still recovering,” she acknowledged. “I described it to my therapist as an invisible wound on my brain.”
“When I came out of the hospital, I still had ECMO wounds, deep gashes on my legs that affected how fast and how long I could walk,” she said. “I felt like the same thing was going on my brain — a huge cut no one could see.”
Her intention to specialize in psychiatry has become more pressing now that Ramya has realized the impact of trauma on mental health.
“My body failing me was awful, but I could handle it,” she said. “Losing any part of my mind would have been way worse. I want to take care of that in my patients.”
This article first appeared on Medscape.com.
Within minutes of her arrival at Community North Hospital in Indianapolis, Ramya Yeleti’s vital signs plummeted; her pulse was at 45 beats per minute and her ejection fraction was hovering near 10%. “I definitely thought there was a chance I would close my eyes and never open them again, but I only had a few seconds to process that,” she recalled. Then everything went black. Ramya fell unconscious as shock pads were positioned and a swarm of clinicians prepared to insert an Impella heart pump through a catheter into her aorta.
The third-year medical student and aspiring psychiatrist had been doing in-person neurology rotations in July when she began to experience fever and uncontrolled vomiting. Her initial thought was that she must have caught the flu from a patient.
After all, Ramya, along with her father Ram Yeleti, MD, mother Indira, and twin sister Divya, had all weathered COVID-19 in previous months and later tested positive for SARS-CoV-2 antibodies. The only family member who had been spared was her younger brother Rohith.
Indira suffered a severe case, requiring ICU care for 2 days but no ventilator; the others experienced mostly mild symptoms. Ramya — who was studying for her third-year board exams after classes at Marian University College of Osteopathic Medicine in Indianapolis went virtual in March — was left with lingering fatigue; however, her cough and muscle aches abated and her sense of taste and smell returned. When she started rotations, she thought her life was getting back to normal.
Ramya’s flu symptoms did not improve. A university-mandated rapid COVID test came back negative, but 2 more days of vomiting started to worry both her and her father, who is a cardiologist and chief physician executive at Community Health Network in Indianapolis. After Ramya felt some chest pain, she asked her father to listen to her heart. All sounded normal, and Ram prescribed ondansetron for her nausea.
But the antiemetic didn’t work, and by the next morning both father and daughter were convinced that they needed to head to the emergency department.
“I wanted to double-check if I was missing something about her being dehydrated,” Ram told Medscape Medical News. “Several things can cause protracted nausea, like hepatitis, appendicitis, or another infection. I feel terribly guilty I didn’t realize she had a heart condition.”
A surprising turn for the worst
Ramya’s subtle symptoms quickly gave way to the dramatic cardiac crisis that unfolded just after her arrival at Community North. “Her EKG looked absolutely horrendous, like a 75-year-old having a heart attack,” Ram said.
As a cardiologist, he knew his daughter’s situation was growing dire when he heard physicians shouting that the Impella wasn’t working and she needed extracorporeal membrane oxygenation (ECMO).
“At that point, I didn’t think she’d survive,” her father recalled. “We had 10 physicians in the room who worked on her for 5 hours to get her stabilized.”
“It was especially traumatic because, obviously, I knew exactly what was happening,” he added. “You can’t sugarcoat anything.”
After being connected to the heart–lung equipment, Ramya was transferred to IU Health Methodist Hospital, also in Indianapolis, where she was tested again for COVID-19. Unlike the rapid test administered just days earlier, the PCR assay came back positive.
“I knew she had acute myocarditis, but coronavirus never crossed my mind,” said Ram.
“As we were dealing with her heart, we were also dealing with this challenge: she was coming back positive for COVID-19 again,” said Roopa Rao, MD, the heart failure transplant cardiologist at IU Health who treated Ramya.
“We weren’t sure whether we were dealing with an active infection or dead virus” from her previous infection, Rao said, “so we started treating her like she had active COVID-19 and gave her remdesivir, convalescent plasma, and steroids, which was the protocol in our hospital.”
A biopsy of Ramya’s heart tissue, along with blood tests, indicated a past parvovirus infection. It’s possible that Ramya’s previous coronavirus infection made her susceptible to heart damage from a newer parvovirus infection, said Rao. Either virus, or both together, could have been responsible for the calamity.
Although it was unheard of during Ramya’s cardiac crisis in early August, evolving evidence now raises the possibility that she is one of a handful of people in the world to be reinfected with SARS-CoV-2. Also emerging are cases of COVID-related myocarditis and other extreme heart complications, particularly in young people.
“At the time, it wasn’t really clear if people could have another infection so quickly,” Rao told Medscape Medical News. “It is possible she is one of these rare individuals to have COVID-19 twice. I’m hoping at some point we will have some clarity.”
“I would favor a coinfection as probably the triggering factor for her sickness,” she said. “It may take some time, but like any other disease — and it doesn’t look like COVID will go away magically — I hope we’ll have some answers down the road.”
Another wrinkle
The next 48 hours brought astonishing news: Ramya’s heart function had rebounded to nearly normal, and her ejection fraction increased to about 45%. Heart transplantation wouldn’t be necessary, although Rao stood poised to follow through if ECMO only sustained, rather than improved, Ramya’s prognosis.
“Ramya was so sick that if she didn’t recover, the only option would be a heart transplant,” said Rao. “But we wanted to do everything to keep that heart.”
After steroid and COVID treatment, Ramya’s heart started to come back. “It didn’t make sense to me,” said Rao. “I don’t know what helped. If we hadn’t done ECMO, her heart probably wouldn’t have recovered, so I would say we have to support these patients and give them time for the heart to recover, even to the point of ECMO.”
Despite the good news, Ramya’s survival still hung in the balance. When she was disconnected from ECMO, clinicians discovered that the Impella device had caused a rare complication, damaging her mitral valve. The valve could be repaired surgically, but both Rao and Ram felt great trepidation at the prospect of cardiopulmonary bypass during the open-heart procedure.
“They would need to stop her heart and restart it, and I was concerned it would not restart,” Ram explained. “I didn’t like the idea of open-heart surgery, but my biggest fear was she was not going to survive it because of a really fresh, sick heart.”
The cardiologists’ fears did, in fact, come to pass: it took an hour to coax Ramya’s heart back at the end of surgery. But, just as the surgeon was preparing to reconnect Ramya to ECMO in desperation, “her heart recovered again,” Rao reported.
“Some things you never forget in life,” she said. “I can’t describe how everyone in the OR felt, all taking care of her. I told Ramya, ‘you are a fighter’.”
New strength
Six days would pass before Ramya woke up and learned of the astounding series of events that saved her. She knew “something was really wrong” because of the incision at the center of her chest, but learning she’d been on ECMO and the heart transplant list drove home how close to death she’d actually come.
“Most people don’t get off ECMO; they die on it,” she said. “And the chances of dying on the heart transplant list are very high. It was very strange to me that this was my story all of a sudden, when a week and a half earlier I was on rotation.”
Ongoing physical therapy over the past 3 months has transformed Ramya from a state of profound physical weakness to a place of relative strength. The now-fourth-year med student is turning 26 in November and is hungry to restart in-person rotations. Her downtime has been filled in part with researching myocarditis and collaborating with Rao on her own case study for journal publication.
But the mental trauma from her experience has girded her in ways she knows will make her stronger personally and professionally in the years ahead.
“It’s still very hard. I’m still recovering,” she acknowledged. “I described it to my therapist as an invisible wound on my brain.”
“When I came out of the hospital, I still had ECMO wounds, deep gashes on my legs that affected how fast and how long I could walk,” she said. “I felt like the same thing was going on my brain — a huge cut no one could see.”
Her intention to specialize in psychiatry has become more pressing now that Ramya has realized the impact of trauma on mental health.
“My body failing me was awful, but I could handle it,” she said. “Losing any part of my mind would have been way worse. I want to take care of that in my patients.”
This article first appeared on Medscape.com.
Within minutes of her arrival at Community North Hospital in Indianapolis, Ramya Yeleti’s vital signs plummeted; her pulse was at 45 beats per minute and her ejection fraction was hovering near 10%. “I definitely thought there was a chance I would close my eyes and never open them again, but I only had a few seconds to process that,” she recalled. Then everything went black. Ramya fell unconscious as shock pads were positioned and a swarm of clinicians prepared to insert an Impella heart pump through a catheter into her aorta.
The third-year medical student and aspiring psychiatrist had been doing in-person neurology rotations in July when she began to experience fever and uncontrolled vomiting. Her initial thought was that she must have caught the flu from a patient.
After all, Ramya, along with her father Ram Yeleti, MD, mother Indira, and twin sister Divya, had all weathered COVID-19 in previous months and later tested positive for SARS-CoV-2 antibodies. The only family member who had been spared was her younger brother Rohith.
Indira suffered a severe case, requiring ICU care for 2 days but no ventilator; the others experienced mostly mild symptoms. Ramya — who was studying for her third-year board exams after classes at Marian University College of Osteopathic Medicine in Indianapolis went virtual in March — was left with lingering fatigue; however, her cough and muscle aches abated and her sense of taste and smell returned. When she started rotations, she thought her life was getting back to normal.
Ramya’s flu symptoms did not improve. A university-mandated rapid COVID test came back negative, but 2 more days of vomiting started to worry both her and her father, who is a cardiologist and chief physician executive at Community Health Network in Indianapolis. After Ramya felt some chest pain, she asked her father to listen to her heart. All sounded normal, and Ram prescribed ondansetron for her nausea.
But the antiemetic didn’t work, and by the next morning both father and daughter were convinced that they needed to head to the emergency department.
“I wanted to double-check if I was missing something about her being dehydrated,” Ram told Medscape Medical News. “Several things can cause protracted nausea, like hepatitis, appendicitis, or another infection. I feel terribly guilty I didn’t realize she had a heart condition.”
A surprising turn for the worst
Ramya’s subtle symptoms quickly gave way to the dramatic cardiac crisis that unfolded just after her arrival at Community North. “Her EKG looked absolutely horrendous, like a 75-year-old having a heart attack,” Ram said.
As a cardiologist, he knew his daughter’s situation was growing dire when he heard physicians shouting that the Impella wasn’t working and she needed extracorporeal membrane oxygenation (ECMO).
“At that point, I didn’t think she’d survive,” her father recalled. “We had 10 physicians in the room who worked on her for 5 hours to get her stabilized.”
“It was especially traumatic because, obviously, I knew exactly what was happening,” he added. “You can’t sugarcoat anything.”
After being connected to the heart–lung equipment, Ramya was transferred to IU Health Methodist Hospital, also in Indianapolis, where she was tested again for COVID-19. Unlike the rapid test administered just days earlier, the PCR assay came back positive.
“I knew she had acute myocarditis, but coronavirus never crossed my mind,” said Ram.
“As we were dealing with her heart, we were also dealing with this challenge: she was coming back positive for COVID-19 again,” said Roopa Rao, MD, the heart failure transplant cardiologist at IU Health who treated Ramya.
“We weren’t sure whether we were dealing with an active infection or dead virus” from her previous infection, Rao said, “so we started treating her like she had active COVID-19 and gave her remdesivir, convalescent plasma, and steroids, which was the protocol in our hospital.”
A biopsy of Ramya’s heart tissue, along with blood tests, indicated a past parvovirus infection. It’s possible that Ramya’s previous coronavirus infection made her susceptible to heart damage from a newer parvovirus infection, said Rao. Either virus, or both together, could have been responsible for the calamity.
Although it was unheard of during Ramya’s cardiac crisis in early August, evolving evidence now raises the possibility that she is one of a handful of people in the world to be reinfected with SARS-CoV-2. Also emerging are cases of COVID-related myocarditis and other extreme heart complications, particularly in young people.
“At the time, it wasn’t really clear if people could have another infection so quickly,” Rao told Medscape Medical News. “It is possible she is one of these rare individuals to have COVID-19 twice. I’m hoping at some point we will have some clarity.”
“I would favor a coinfection as probably the triggering factor for her sickness,” she said. “It may take some time, but like any other disease — and it doesn’t look like COVID will go away magically — I hope we’ll have some answers down the road.”
Another wrinkle
The next 48 hours brought astonishing news: Ramya’s heart function had rebounded to nearly normal, and her ejection fraction increased to about 45%. Heart transplantation wouldn’t be necessary, although Rao stood poised to follow through if ECMO only sustained, rather than improved, Ramya’s prognosis.
“Ramya was so sick that if she didn’t recover, the only option would be a heart transplant,” said Rao. “But we wanted to do everything to keep that heart.”
After steroid and COVID treatment, Ramya’s heart started to come back. “It didn’t make sense to me,” said Rao. “I don’t know what helped. If we hadn’t done ECMO, her heart probably wouldn’t have recovered, so I would say we have to support these patients and give them time for the heart to recover, even to the point of ECMO.”
Despite the good news, Ramya’s survival still hung in the balance. When she was disconnected from ECMO, clinicians discovered that the Impella device had caused a rare complication, damaging her mitral valve. The valve could be repaired surgically, but both Rao and Ram felt great trepidation at the prospect of cardiopulmonary bypass during the open-heart procedure.
“They would need to stop her heart and restart it, and I was concerned it would not restart,” Ram explained. “I didn’t like the idea of open-heart surgery, but my biggest fear was she was not going to survive it because of a really fresh, sick heart.”
The cardiologists’ fears did, in fact, come to pass: it took an hour to coax Ramya’s heart back at the end of surgery. But, just as the surgeon was preparing to reconnect Ramya to ECMO in desperation, “her heart recovered again,” Rao reported.
“Some things you never forget in life,” she said. “I can’t describe how everyone in the OR felt, all taking care of her. I told Ramya, ‘you are a fighter’.”
New strength
Six days would pass before Ramya woke up and learned of the astounding series of events that saved her. She knew “something was really wrong” because of the incision at the center of her chest, but learning she’d been on ECMO and the heart transplant list drove home how close to death she’d actually come.
“Most people don’t get off ECMO; they die on it,” she said. “And the chances of dying on the heart transplant list are very high. It was very strange to me that this was my story all of a sudden, when a week and a half earlier I was on rotation.”
Ongoing physical therapy over the past 3 months has transformed Ramya from a state of profound physical weakness to a place of relative strength. The now-fourth-year med student is turning 26 in November and is hungry to restart in-person rotations. Her downtime has been filled in part with researching myocarditis and collaborating with Rao on her own case study for journal publication.
But the mental trauma from her experience has girded her in ways she knows will make her stronger personally and professionally in the years ahead.
“It’s still very hard. I’m still recovering,” she acknowledged. “I described it to my therapist as an invisible wound on my brain.”
“When I came out of the hospital, I still had ECMO wounds, deep gashes on my legs that affected how fast and how long I could walk,” she said. “I felt like the same thing was going on my brain — a huge cut no one could see.”
Her intention to specialize in psychiatry has become more pressing now that Ramya has realized the impact of trauma on mental health.
“My body failing me was awful, but I could handle it,” she said. “Losing any part of my mind would have been way worse. I want to take care of that in my patients.”
This article first appeared on Medscape.com.
Understand the legal implications of telehealth medicine
Telehealth has been steadily gaining mainstream use throughout the last decade, but the practice was recently shoved, almost overnight, into the forefront of the health care profession. Telehealth is now used more frequently by medical groups and physicians than ever before. General reports before the COVID-19 pandemic approximated 90% of health care organizations used or planned to use telehealth in the future. This future may already be a reality, with a McKinsey & Company report estimating that physicians saw 50-175 times more patients over telehealth platforms since the pandemic’s start.1
In general, telehealth includes use of electronic communication and information technologies to deliver long-distance or remote health care. A physician’s use of telemedicine (clinical services) is one of the most common uses, but the industry also includes other professionals, such as pharmacists and nurses.
Telehealth platforms can be used to monitor, diagnose, treat, and counsel patients successfully. It works best for reading images, follow-up care, outpatient care, and long-term care. However, telemedicine is inappropriate for urgent issues, diagnosing underlying health conditions, or any practice where the standard of care would require a physical exam. There is potential liability for decision making without a proper physical exam. 
There are many advantages to telehealth over more traditional health care options. Some of these advantages include:
- Increased access to health care.
- Increased access to medical specialists in small and rural communities.
- Improved long-term care from the comfort of patients’ homes.
- Improved platforms to document patient care outside regular business hours.
But along with these benefits, telehealth carries the disadvantage of potential increased liability. This increased liability could stem from:
- Breached standards of care.
- Inadequate or improper licensing.
- Limited care options.
- Decision making without a proper physical exam.
- Increased informed consent requirements.
- Restricted prescription access.
Before expanding any practice into telemedicine, awareness of potential legal issues is crucial.
Standard of care
Currently, telehealth laws and regulations vary significantly from state to state. But one rule is consistent across the board – that the standard of care for practicing medicine through telemedicine is identical to the standard of care required for practicing medicine during physical practice. It still requires the appropriate examination, testing, labs, imaging, and consultations that any in-person diagnosis needs. For physicians, it also includes supervising nonphysician clinicians, where state law requires supervision.
The American Telemedicine Association currently determines the primary governing standards and guidelines for telemedicine. These can help physicians understand best practices in meeting the standard of care through telemedicine. The American Gastroenterological Association provides coding guidelines and other resources to help physicians with telehealth and e-visits. Other professional societies, such as the American College of Radiology and the American Academy of Dermatology, offer guidelines specific to their medical specialties’ standards of care. These standards still vary from state to state, so medical professionals must be aware of any differences before treating patients in multiple states.
Licensing
Licensing is one of telemedicine’s most confusing legal issues. All states require a license to practice medicine (traditional or telehealth) within their borders. Without that license, practicing medicine in the state is a crime. On top of being criminal, unlicensed practice can affect insurance, liability, billing, and malpractice coverage. When in a brick-and-mortar clinic, a physician’s confidence in practicing within the licensed jurisdiction is easy. Now, the distinction is not so clear. Patients and physicians no longer have to be in the same room, city, or even state, meaning there could be unknown conflicting laws between the two locations. With rare exceptions, standards of care are based on the patient’s location, not the physician’s location. This increases the risk of practicing without being correctly licensed to higher than ever.
Because licensing is a significant roadblock in providing telemedicine, efforts are underway to make the process simpler and more streamlined. The Federation of State Medical Boards developed the Interstate Medical Licensure Compact (IMLC).2 This can qualify physicians to practice medicine across state lines within the compact so long as they meet specific eligibility requirements. The IMLC creates a fast-track option for physicians to fill out one application and receive licenses from multiple states at once. Currently, the compact includes 32 states, the District of Columbia, and Guam.3
Informed consent
Telemedicine health care still requires informed consent from patients. In fact, in some states, the requirements for care provided through telehealth are actually stricter than requirements for informed consent obtained in person.
Most informed consent laws require physicians to cover the risks and benefits of a recommended course of treatment and all feasible and reasonable material alternatives. On top of this traditional informed consent, physicians must get additional consent to receive care over a telehealth platform. This unique requirement explains what telehealth is, possible risks and expected benefits, and security measures used to protect patient information. States vary regarding when verbal consent is sufficient, and when written consent is required.
Prescriptions
Telemedicine is still a relatively new industry, and few legal opinions specifically address telemedicine malpractice. However, prescribing medication based on telemedicine information is among the few issues the courts have addressed. A 2008 decision found that a physician review of patient questionnaires submitted over the Internet was insufficient to prescribe medication without a physical examination determining patient health.4 This cautious approach stemmed from telehealth’s early concern about the absence of patient-physician relationships and potential online pharmacy abuse. Since this decision, many states require an “in-person” visit with a patient before prescribing medication. The definition of what qualifies as an in-person visit varies from state to state – some still consider the use of real-time, audiovisual conferencing sufficient.
The law is still evolving for prescriptions. Some states don’t allow any prescriptions, while others allow physicians to prescribe their patients’ medications as part of an appropriate treatment plan according to their professional discretion. Almost every state prohibits the prescription of controlled substances based on telemedicine.
Conclusion
Telemedicine is becoming an increasingly significant part of both physician-patient relationships and the broader health care industry. Used appropriately, it can be an incredibly effective method of care for physicians and patients. Physicians should learn the laws governing telemedicine in every state they want to practice and continue to stay current on any changes. The Center for Connected Health Policy offers a report, updated semiannually, to help physicians stay up to date on their state laws. These efforts will help prevent physicians from exposure to liability and medical malpractice claims.
Mr. Hyde is a partner at Younker Hyde Macfarlane, a law firm that focuses on prosecuting medical malpractice claims on behalf of injured patients. Ms. Johnson is an associate attorney with the firm. You can find them at YHMLaw.com.
References
1. Bestsennyy O, Harris A, Rost J. Telehealth: A quarter-trillion-dollar post-COVID-19 reality? Mckinsey & Company, May 29, 2020.
2. FSMB: Draft Interstate Compact for Physician Licensure Nears Completion, 2014.
3. Interstate Medical Licensure Compact: U.S. State Participation in the Compact.
4. See, Low Cost Pharm., Inc. v. Ariz. State Bd. Of Pharm, 2008 Ariz. App. Unpub. LEXIS 790, referencing conclusion of Arizona Medical Board.
Telehealth has been steadily gaining mainstream use throughout the last decade, but the practice was recently shoved, almost overnight, into the forefront of the health care profession. Telehealth is now used more frequently by medical groups and physicians than ever before. General reports before the COVID-19 pandemic approximated 90% of health care organizations used or planned to use telehealth in the future. This future may already be a reality, with a McKinsey & Company report estimating that physicians saw 50-175 times more patients over telehealth platforms since the pandemic’s start.1
In general, telehealth includes use of electronic communication and information technologies to deliver long-distance or remote health care. A physician’s use of telemedicine (clinical services) is one of the most common uses, but the industry also includes other professionals, such as pharmacists and nurses.
Telehealth platforms can be used to monitor, diagnose, treat, and counsel patients successfully. It works best for reading images, follow-up care, outpatient care, and long-term care. However, telemedicine is inappropriate for urgent issues, diagnosing underlying health conditions, or any practice where the standard of care would require a physical exam. There is potential liability for decision making without a proper physical exam.
There are many advantages to telehealth over more traditional health care options. Some of these advantages include:
- Increased access to health care.
- Increased access to medical specialists in small and rural communities.
- Improved long-term care from the comfort of patients’ homes.
- Improved platforms to document patient care outside regular business hours.
But along with these benefits, telehealth carries the disadvantage of potential increased liability. This increased liability could stem from:
- Breached standards of care.
- Inadequate or improper licensing.
- Limited care options.
- Decision making without a proper physical exam.
- Increased informed consent requirements.
- Restricted prescription access.
Before expanding any practice into telemedicine, awareness of potential legal issues is crucial.
Standard of care
Currently, telehealth laws and regulations vary significantly from state to state. But one rule is consistent across the board – that the standard of care for practicing medicine through telemedicine is identical to the standard of care required for practicing medicine during physical practice. It still requires the appropriate examination, testing, labs, imaging, and consultations that any in-person diagnosis needs. For physicians, it also includes supervising nonphysician clinicians, where state law requires supervision.
The American Telemedicine Association currently determines the primary governing standards and guidelines for telemedicine. These can help physicians understand best practices in meeting the standard of care through telemedicine. The American Gastroenterological Association provides coding guidelines and other resources to help physicians with telehealth and e-visits. Other professional societies, such as the American College of Radiology and the American Academy of Dermatology, offer guidelines specific to their medical specialties’ standards of care. These standards still vary from state to state, so medical professionals must be aware of any differences before treating patients in multiple states.
Licensing
Licensing is one of telemedicine’s most confusing legal issues. All states require a license to practice medicine (traditional or telehealth) within their borders. Without that license, practicing medicine in the state is a crime. On top of being criminal, unlicensed practice can affect insurance, liability, billing, and malpractice coverage. When in a brick-and-mortar clinic, a physician’s confidence in practicing within the licensed jurisdiction is easy. Now, the distinction is not so clear. Patients and physicians no longer have to be in the same room, city, or even state, meaning there could be unknown conflicting laws between the two locations. With rare exceptions, standards of care are based on the patient’s location, not the physician’s location. This increases the risk of practicing without being correctly licensed to higher than ever.
Because licensing is a significant roadblock in providing telemedicine, efforts are underway to make the process simpler and more streamlined. The Federation of State Medical Boards developed the Interstate Medical Licensure Compact (IMLC).2 This can qualify physicians to practice medicine across state lines within the compact so long as they meet specific eligibility requirements. The IMLC creates a fast-track option for physicians to fill out one application and receive licenses from multiple states at once. Currently, the compact includes 32 states, the District of Columbia, and Guam.3
Informed consent
Telemedicine health care still requires informed consent from patients. In fact, in some states, the requirements for care provided through telehealth are actually stricter than requirements for informed consent obtained in person.
Most informed consent laws require physicians to cover the risks and benefits of a recommended course of treatment and all feasible and reasonable material alternatives. On top of this traditional informed consent, physicians must get additional consent to receive care over a telehealth platform. This unique requirement explains what telehealth is, possible risks and expected benefits, and security measures used to protect patient information. States vary regarding when verbal consent is sufficient, and when written consent is required.
Prescriptions
Telemedicine is still a relatively new industry, and few legal opinions specifically address telemedicine malpractice. However, prescribing medication based on telemedicine information is among the few issues the courts have addressed. A 2008 decision found that a physician review of patient questionnaires submitted over the Internet was insufficient to prescribe medication without a physical examination determining patient health.4 This cautious approach stemmed from telehealth’s early concern about the absence of patient-physician relationships and potential online pharmacy abuse. Since this decision, many states require an “in-person” visit with a patient before prescribing medication. The definition of what qualifies as an in-person visit varies from state to state – some still consider the use of real-time, audiovisual conferencing sufficient.
The law is still evolving for prescriptions. Some states don’t allow any prescriptions, while others allow physicians to prescribe their patients’ medications as part of an appropriate treatment plan according to their professional discretion. Almost every state prohibits the prescription of controlled substances based on telemedicine.
Conclusion
Telemedicine is becoming an increasingly significant part of both physician-patient relationships and the broader health care industry. Used appropriately, it can be an incredibly effective method of care for physicians and patients. Physicians should learn the laws governing telemedicine in every state they want to practice and continue to stay current on any changes. The Center for Connected Health Policy offers a report, updated semiannually, to help physicians stay up to date on their state laws. These efforts will help prevent physicians from exposure to liability and medical malpractice claims.
Mr. Hyde is a partner at Younker Hyde Macfarlane, a law firm that focuses on prosecuting medical malpractice claims on behalf of injured patients. Ms. Johnson is an associate attorney with the firm. You can find them at YHMLaw.com.
References
1. Bestsennyy O, Harris A, Rost J. Telehealth: A quarter-trillion-dollar post-COVID-19 reality? Mckinsey & Company, May 29, 2020.
2. FSMB: Draft Interstate Compact for Physician Licensure Nears Completion, 2014.
3. Interstate Medical Licensure Compact: U.S. State Participation in the Compact.
4. See, Low Cost Pharm., Inc. v. Ariz. State Bd. Of Pharm, 2008 Ariz. App. Unpub. LEXIS 790, referencing conclusion of Arizona Medical Board.
Telehealth has been steadily gaining mainstream use throughout the last decade, but the practice was recently shoved, almost overnight, into the forefront of the health care profession. Telehealth is now used more frequently by medical groups and physicians than ever before. General reports before the COVID-19 pandemic approximated 90% of health care organizations used or planned to use telehealth in the future. This future may already be a reality, with a McKinsey & Company report estimating that physicians saw 50-175 times more patients over telehealth platforms since the pandemic’s start.1
In general, telehealth includes use of electronic communication and information technologies to deliver long-distance or remote health care. A physician’s use of telemedicine (clinical services) is one of the most common uses, but the industry also includes other professionals, such as pharmacists and nurses.
Telehealth platforms can be used to monitor, diagnose, treat, and counsel patients successfully. It works best for reading images, follow-up care, outpatient care, and long-term care. However, telemedicine is inappropriate for urgent issues, diagnosing underlying health conditions, or any practice where the standard of care would require a physical exam. There is potential liability for decision making without a proper physical exam.
There are many advantages to telehealth over more traditional health care options. Some of these advantages include:
- Increased access to health care.
- Increased access to medical specialists in small and rural communities.
- Improved long-term care from the comfort of patients’ homes.
- Improved platforms to document patient care outside regular business hours.
But along with these benefits, telehealth carries the disadvantage of potential increased liability. This increased liability could stem from:
- Breached standards of care.
- Inadequate or improper licensing.
- Limited care options.
- Decision making without a proper physical exam.
- Increased informed consent requirements.
- Restricted prescription access.
Before expanding any practice into telemedicine, awareness of potential legal issues is crucial.
Standard of care
Currently, telehealth laws and regulations vary significantly from state to state. But one rule is consistent across the board – that the standard of care for practicing medicine through telemedicine is identical to the standard of care required for practicing medicine during physical practice. It still requires the appropriate examination, testing, labs, imaging, and consultations that any in-person diagnosis needs. For physicians, it also includes supervising nonphysician clinicians, where state law requires supervision.
The American Telemedicine Association currently determines the primary governing standards and guidelines for telemedicine. These can help physicians understand best practices in meeting the standard of care through telemedicine. The American Gastroenterological Association provides coding guidelines and other resources to help physicians with telehealth and e-visits. Other professional societies, such as the American College of Radiology and the American Academy of Dermatology, offer guidelines specific to their medical specialties’ standards of care. These standards still vary from state to state, so medical professionals must be aware of any differences before treating patients in multiple states.
Licensing
Licensing is one of telemedicine’s most confusing legal issues. All states require a license to practice medicine (traditional or telehealth) within their borders. Without that license, practicing medicine in the state is a crime. On top of being criminal, unlicensed practice can affect insurance, liability, billing, and malpractice coverage. When in a brick-and-mortar clinic, a physician’s confidence in practicing within the licensed jurisdiction is easy. Now, the distinction is not so clear. Patients and physicians no longer have to be in the same room, city, or even state, meaning there could be unknown conflicting laws between the two locations. With rare exceptions, standards of care are based on the patient’s location, not the physician’s location. This increases the risk of practicing without being correctly licensed to higher than ever.
Because licensing is a significant roadblock in providing telemedicine, efforts are underway to make the process simpler and more streamlined. The Federation of State Medical Boards developed the Interstate Medical Licensure Compact (IMLC).2 This can qualify physicians to practice medicine across state lines within the compact so long as they meet specific eligibility requirements. The IMLC creates a fast-track option for physicians to fill out one application and receive licenses from multiple states at once. Currently, the compact includes 32 states, the District of Columbia, and Guam.3
Informed consent
Telemedicine health care still requires informed consent from patients. In fact, in some states, the requirements for care provided through telehealth are actually stricter than requirements for informed consent obtained in person.
Most informed consent laws require physicians to cover the risks and benefits of a recommended course of treatment and all feasible and reasonable material alternatives. On top of this traditional informed consent, physicians must get additional consent to receive care over a telehealth platform. This unique requirement explains what telehealth is, possible risks and expected benefits, and security measures used to protect patient information. States vary regarding when verbal consent is sufficient, and when written consent is required.
Prescriptions
Telemedicine is still a relatively new industry, and few legal opinions specifically address telemedicine malpractice. However, prescribing medication based on telemedicine information is among the few issues the courts have addressed. A 2008 decision found that a physician review of patient questionnaires submitted over the Internet was insufficient to prescribe medication without a physical examination determining patient health.4 This cautious approach stemmed from telehealth’s early concern about the absence of patient-physician relationships and potential online pharmacy abuse. Since this decision, many states require an “in-person” visit with a patient before prescribing medication. The definition of what qualifies as an in-person visit varies from state to state – some still consider the use of real-time, audiovisual conferencing sufficient.
The law is still evolving for prescriptions. Some states don’t allow any prescriptions, while others allow physicians to prescribe their patients’ medications as part of an appropriate treatment plan according to their professional discretion. Almost every state prohibits the prescription of controlled substances based on telemedicine.
Conclusion
Telemedicine is becoming an increasingly significant part of both physician-patient relationships and the broader health care industry. Used appropriately, it can be an incredibly effective method of care for physicians and patients. Physicians should learn the laws governing telemedicine in every state they want to practice and continue to stay current on any changes. The Center for Connected Health Policy offers a report, updated semiannually, to help physicians stay up to date on their state laws. These efforts will help prevent physicians from exposure to liability and medical malpractice claims.
Mr. Hyde is a partner at Younker Hyde Macfarlane, a law firm that focuses on prosecuting medical malpractice claims on behalf of injured patients. Ms. Johnson is an associate attorney with the firm. You can find them at YHMLaw.com.
References
1. Bestsennyy O, Harris A, Rost J. Telehealth: A quarter-trillion-dollar post-COVID-19 reality? Mckinsey & Company, May 29, 2020.
2. FSMB: Draft Interstate Compact for Physician Licensure Nears Completion, 2014.
3. Interstate Medical Licensure Compact: U.S. State Participation in the Compact.
4. See, Low Cost Pharm., Inc. v. Ariz. State Bd. Of Pharm, 2008 Ariz. App. Unpub. LEXIS 790, referencing conclusion of Arizona Medical Board.