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Systemic therapies are impacting melanoma’s prognostic factors
As systemic therapies for advanced melanoma increase, some historical prognostic factors continue to hold true while refined and novel risk factors are emerging, according to the results of three studies published in JAMA Dermatology.
Among the most prominent findings of those studies are that ulceration, mitotic index, and head and neck location in localized disease were predictive of early recurrence; time to recurrence was not associated with survival in unresectable stage IV melanoma; and certain gene markers may be linked with particular types of metastasis.
The first study, conducted by Lena A. von Schuckmann, MBBS, of the University of Queensland School of Public Health in Australia, and colleagues, evaluated the risk of early melanoma recurrence in patients with localized disease.
“With the introduction of targeted and immune therapies for treatment of metastatic melanoma, including possible adjuvant therapy, a detailed understanding of the risk of melanoma recurrence may assist clinicians to advise patients with a primary tumor at high risk of disease metastasis,” the researchers wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0440).
They conducted a prospective cohort study of 700 patients with high-risk, category T1b to T4b cutaneous melanoma, refined from an initial recruitment population of 1,254 individuals. Using self-administered patient questionnaires in conjunction with histologic, imaging, and clinical data over the course of 2 years, the investigators looked for factors that predicted recurrence.
Of 700 patients, 94 (13.4%) had disease recurrence, most often (70.2%) locoregional recurrence. Independent predictors of recurrence included mitotic rate greater than 3/mm2, thickness, ulceration, and primary tumor location on the head or neck.
Patients with negative single lymph node biopsy (SLNB) were less likely to have recurrence than were those who did not undergo SLNB. Among 64 patients whose locoregional disease was excised, 37 (57.8%) were disease free at 2 years, whereas 7 patients (10.9%) had new locoregional disease and 20 patients (31.3%) developed a new distant recurrence.
“[O]ur data appear to support the recommendation for careful scar and regional skin and lymph node examination during patient follow-up,” the investigators concluded, alluding to the relatively high rate of locoregional recurrence. “Subsequent recurrences occurring at distant sites were more likely to involve multiple organs, which is consistent with other studies.”
The second melanoma article, investigating associations between time to relapse and survival, was authored by Anaïs Vallet, MD, of Hôpital Saint-Louis, Paris, and colleagues.
“Although the kinetics of metastatic disease seem to be correlated with patient survival, the first relapse is not predictable, and data from the literature on the topic are controversial,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0425). “We hypothesized that the progression of the metastatic disease would be associated with the time from primary excision to the first distant recurrence of melanoma.”
To test this hypothesis, the investigators analyzed data from 638 patients with unresectable stage III or IV melanoma. Inclusion required first-line treatment with chemotherapy, targeted therapies, or immunotherapies. The interval between primary excision and distant disease recurrence, measured as a categorical and continuous variable, was compared with overall survival and progression-free survival. The analysis revealed no associations between time to recurrence and either survival measure, even when stratified by treatment.
“Now that immunotherapies and targeted therapies have been approved in the adjuvant setting for patients with stage III disease, it would be interesting to analyze recurrence-free survival and [progression-free survival] in relapsing patients who previously received adjuvant therapies,” the investigators wrote.
The third study was conducted by Laura Calomarde-Rees, MD, of Instituto Valenciano de Oncología, València, Spain, and colleagues.
“Our aim was to identify risk factors associated with lymphatic (locoregional metastasis) or hematogenous (distant metastasis) progression because these have not been studied separately to date in patients with localized melanoma,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0069).
The retrospective study involved 1,177 patients with stage I to II melanoma. Multiple disease variables were evaluated in the context of each type of metastasis, including age, sex, tumor location, and others.
The investigators found locoregional spread was most often associated with vascular invasion (hazard ratio [HR], 3.2), greater Breslow thickness (HR, 5.4; thickness greater than 4 mm), acral location (HR, 2.4), head/neck location (HR, 1.7), and age greater than 55 years (HR, 1.9).
Distant metastasis was most often associated with greater Breslow thickness (HR, 10.4; thickness greater than 4 mm), TERT promoter mutations (HR, 2.9), BRAF mutations (HR, 1.9), and absence of regression (HR, 0.1).
“Risk factors for lymphatic and hematogenous metastasis differ,” the investigators concluded. “A greater understanding of the clinical, histopathologic, and molecular factors involved could help to identify patients with an increased risk of recurrence and guide the design of individualized follow-up programs and adjuvant targeted therapies.”
Dr. von Schuckmann and colleagues disclosed study funding from the National Health and Medical Research Council and other relationships with the Norwegian Cancer Society project. Dr. Vallet and colleagues reported study support from French National Cancer Institute, MSD, BMS, Roche, and Novartis; and additional relationships with Incyte, Amgen, Pfizer, and others. Dr. Calomarde-Rees and colleagues disclosed no conflicts of interest.
Effective systemic treatments have forever altered the kinetics of events in advanced melanoma, with the natural history outcome curves of this cancer now highly dependent on treatment response. The relapse-free survival (RFS) curves of patients with stage IIC/III melanoma with and without adjuvant dabrafenib/trametinib demonstrate the contemporary natural history of frequent early recurrences with few late events in the placebo groups and of fewer and later recurrences, with an as yet unknown frequency of late events, in the treated groups.
The three reported studies examine melanoma disease kinetics and speak to this new paradigm.
The first study, conducted by von Schuckmann and colleagues, looked for factors associated with disease recurrence within 2 years of treatment for localized, T1b to T4b melanoma.
Factors were not surprising and included the presence of ulceration, an increased mitotic index, increasing T stage, and location on the head and neck. Also, the study had two major limitations. First, the patient population was a heterogenous one – 442 patients with clinical T1b to T4b did not undergo sentinel lymph node biopsy (SLNB), 213 patients with pathologic T1b to T4b had a negative SLNB result, and 38 patients had at least stage IIIa disease after a positive SLNB finding. Second, as the 8th edition of the AJCC [American Joint Committee on Cancer] Staging Manual notes, most events in this cohort of patients are expected to occur after the 2-year threshold described in this prospective study and the disease can recur as much as 10 years after effective treatment.
The second study, conducted by Vallet and colleagues, analyzed data from patients with unresectable stage IV melanoma to determine if time to distant recurrence after excision of antecedent primary melanoma was associated with survival.
Time to first distant metastasis was not related to Breslow thickness or to tumor stage at the start of therapy; however, the data analysis did not include multiple patient variables that might have shed more light on predictive factors.
As systemic therapy increasingly leads to stabilization of previously progressive disease as well as durable complete remissions in melanoma patients, best response to immunotherapy or targeted therapy is likely to emerge as a much more important predictor than the time it took for stage IV melanoma to become apparent. There has been some thoughtful interest in exploring the prognostic value of establishing the kinetics of stage IV melanoma as a prognostic factor prior to initiating therapy, but there has been limited uptake of this approach by the melanoma oncology community.
In the third study, Calomarde-Rees and colleagues explored associations between melanoma disease characteristics and hematogenous or lymphatic metastases.
The anticipated findings include the observed association between tumor thickness and risk of recurrence, either lymphatic or hematogenous. As satellitosis is already considered a criterion for stage III in AJCC8, these two observations serve as internal controls that validate the credibility of the data set.
The researchers’ most intriguing finding is the strong potential association of the combination of both MAPK (either BRAF or NRAS) and TERT promoter mutations with poor survival, as demonstrated in their second prognostic model (hazard ratio, 5.7). This finding warrants cautious interpretation as the authors clearly acknowledge that a minority of the study population underwent detailed assessments of the mutation status of each gene.
While the biologic behavior of melanoma is likely to be much more complex than the mutation of one or two genes, the potential interaction of the mutated TERT promoter gene is provocative, especially in the context of a recent article suggesting a role for monitoring BRAF and TERT circulating free DNA as an indicator of response to systemic therapy and outcome.
Multigene panels are being developed, but it remains to be demonstrated whether any of these highly discrepant gene profiles will outperform optimized contemporary multivariable individual patient risk prediction models across the prognostic spectrum of melanoma.
Daniel G. Coit, MD is a surgical oncologist at Memorial Sloan Kettering Cancer Center in New York. He made his remarks in an editorial in JAMA Dermatology (2019 May 1. doi: 10.1001/jamadermatol.2019.0200). Dr. Coit disclosed that he has no relevant financial conflicts of interest.
Effective systemic treatments have forever altered the kinetics of events in advanced melanoma, with the natural history outcome curves of this cancer now highly dependent on treatment response. The relapse-free survival (RFS) curves of patients with stage IIC/III melanoma with and without adjuvant dabrafenib/trametinib demonstrate the contemporary natural history of frequent early recurrences with few late events in the placebo groups and of fewer and later recurrences, with an as yet unknown frequency of late events, in the treated groups.
The three reported studies examine melanoma disease kinetics and speak to this new paradigm.
The first study, conducted by von Schuckmann and colleagues, looked for factors associated with disease recurrence within 2 years of treatment for localized, T1b to T4b melanoma.
Factors were not surprising and included the presence of ulceration, an increased mitotic index, increasing T stage, and location on the head and neck. Also, the study had two major limitations. First, the patient population was a heterogenous one – 442 patients with clinical T1b to T4b did not undergo sentinel lymph node biopsy (SLNB), 213 patients with pathologic T1b to T4b had a negative SLNB result, and 38 patients had at least stage IIIa disease after a positive SLNB finding. Second, as the 8th edition of the AJCC [American Joint Committee on Cancer] Staging Manual notes, most events in this cohort of patients are expected to occur after the 2-year threshold described in this prospective study and the disease can recur as much as 10 years after effective treatment.
The second study, conducted by Vallet and colleagues, analyzed data from patients with unresectable stage IV melanoma to determine if time to distant recurrence after excision of antecedent primary melanoma was associated with survival.
Time to first distant metastasis was not related to Breslow thickness or to tumor stage at the start of therapy; however, the data analysis did not include multiple patient variables that might have shed more light on predictive factors.
As systemic therapy increasingly leads to stabilization of previously progressive disease as well as durable complete remissions in melanoma patients, best response to immunotherapy or targeted therapy is likely to emerge as a much more important predictor than the time it took for stage IV melanoma to become apparent. There has been some thoughtful interest in exploring the prognostic value of establishing the kinetics of stage IV melanoma as a prognostic factor prior to initiating therapy, but there has been limited uptake of this approach by the melanoma oncology community.
In the third study, Calomarde-Rees and colleagues explored associations between melanoma disease characteristics and hematogenous or lymphatic metastases.
The anticipated findings include the observed association between tumor thickness and risk of recurrence, either lymphatic or hematogenous. As satellitosis is already considered a criterion for stage III in AJCC8, these two observations serve as internal controls that validate the credibility of the data set.
The researchers’ most intriguing finding is the strong potential association of the combination of both MAPK (either BRAF or NRAS) and TERT promoter mutations with poor survival, as demonstrated in their second prognostic model (hazard ratio, 5.7). This finding warrants cautious interpretation as the authors clearly acknowledge that a minority of the study population underwent detailed assessments of the mutation status of each gene.
While the biologic behavior of melanoma is likely to be much more complex than the mutation of one or two genes, the potential interaction of the mutated TERT promoter gene is provocative, especially in the context of a recent article suggesting a role for monitoring BRAF and TERT circulating free DNA as an indicator of response to systemic therapy and outcome.
Multigene panels are being developed, but it remains to be demonstrated whether any of these highly discrepant gene profiles will outperform optimized contemporary multivariable individual patient risk prediction models across the prognostic spectrum of melanoma.
Daniel G. Coit, MD is a surgical oncologist at Memorial Sloan Kettering Cancer Center in New York. He made his remarks in an editorial in JAMA Dermatology (2019 May 1. doi: 10.1001/jamadermatol.2019.0200). Dr. Coit disclosed that he has no relevant financial conflicts of interest.
Effective systemic treatments have forever altered the kinetics of events in advanced melanoma, with the natural history outcome curves of this cancer now highly dependent on treatment response. The relapse-free survival (RFS) curves of patients with stage IIC/III melanoma with and without adjuvant dabrafenib/trametinib demonstrate the contemporary natural history of frequent early recurrences with few late events in the placebo groups and of fewer and later recurrences, with an as yet unknown frequency of late events, in the treated groups.
The three reported studies examine melanoma disease kinetics and speak to this new paradigm.
The first study, conducted by von Schuckmann and colleagues, looked for factors associated with disease recurrence within 2 years of treatment for localized, T1b to T4b melanoma.
Factors were not surprising and included the presence of ulceration, an increased mitotic index, increasing T stage, and location on the head and neck. Also, the study had two major limitations. First, the patient population was a heterogenous one – 442 patients with clinical T1b to T4b did not undergo sentinel lymph node biopsy (SLNB), 213 patients with pathologic T1b to T4b had a negative SLNB result, and 38 patients had at least stage IIIa disease after a positive SLNB finding. Second, as the 8th edition of the AJCC [American Joint Committee on Cancer] Staging Manual notes, most events in this cohort of patients are expected to occur after the 2-year threshold described in this prospective study and the disease can recur as much as 10 years after effective treatment.
The second study, conducted by Vallet and colleagues, analyzed data from patients with unresectable stage IV melanoma to determine if time to distant recurrence after excision of antecedent primary melanoma was associated with survival.
Time to first distant metastasis was not related to Breslow thickness or to tumor stage at the start of therapy; however, the data analysis did not include multiple patient variables that might have shed more light on predictive factors.
As systemic therapy increasingly leads to stabilization of previously progressive disease as well as durable complete remissions in melanoma patients, best response to immunotherapy or targeted therapy is likely to emerge as a much more important predictor than the time it took for stage IV melanoma to become apparent. There has been some thoughtful interest in exploring the prognostic value of establishing the kinetics of stage IV melanoma as a prognostic factor prior to initiating therapy, but there has been limited uptake of this approach by the melanoma oncology community.
In the third study, Calomarde-Rees and colleagues explored associations between melanoma disease characteristics and hematogenous or lymphatic metastases.
The anticipated findings include the observed association between tumor thickness and risk of recurrence, either lymphatic or hematogenous. As satellitosis is already considered a criterion for stage III in AJCC8, these two observations serve as internal controls that validate the credibility of the data set.
The researchers’ most intriguing finding is the strong potential association of the combination of both MAPK (either BRAF or NRAS) and TERT promoter mutations with poor survival, as demonstrated in their second prognostic model (hazard ratio, 5.7). This finding warrants cautious interpretation as the authors clearly acknowledge that a minority of the study population underwent detailed assessments of the mutation status of each gene.
While the biologic behavior of melanoma is likely to be much more complex than the mutation of one or two genes, the potential interaction of the mutated TERT promoter gene is provocative, especially in the context of a recent article suggesting a role for monitoring BRAF and TERT circulating free DNA as an indicator of response to systemic therapy and outcome.
Multigene panels are being developed, but it remains to be demonstrated whether any of these highly discrepant gene profiles will outperform optimized contemporary multivariable individual patient risk prediction models across the prognostic spectrum of melanoma.
Daniel G. Coit, MD is a surgical oncologist at Memorial Sloan Kettering Cancer Center in New York. He made his remarks in an editorial in JAMA Dermatology (2019 May 1. doi: 10.1001/jamadermatol.2019.0200). Dr. Coit disclosed that he has no relevant financial conflicts of interest.
As systemic therapies for advanced melanoma increase, some historical prognostic factors continue to hold true while refined and novel risk factors are emerging, according to the results of three studies published in JAMA Dermatology.
Among the most prominent findings of those studies are that ulceration, mitotic index, and head and neck location in localized disease were predictive of early recurrence; time to recurrence was not associated with survival in unresectable stage IV melanoma; and certain gene markers may be linked with particular types of metastasis.
The first study, conducted by Lena A. von Schuckmann, MBBS, of the University of Queensland School of Public Health in Australia, and colleagues, evaluated the risk of early melanoma recurrence in patients with localized disease.
“With the introduction of targeted and immune therapies for treatment of metastatic melanoma, including possible adjuvant therapy, a detailed understanding of the risk of melanoma recurrence may assist clinicians to advise patients with a primary tumor at high risk of disease metastasis,” the researchers wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0440).
They conducted a prospective cohort study of 700 patients with high-risk, category T1b to T4b cutaneous melanoma, refined from an initial recruitment population of 1,254 individuals. Using self-administered patient questionnaires in conjunction with histologic, imaging, and clinical data over the course of 2 years, the investigators looked for factors that predicted recurrence.
Of 700 patients, 94 (13.4%) had disease recurrence, most often (70.2%) locoregional recurrence. Independent predictors of recurrence included mitotic rate greater than 3/mm2, thickness, ulceration, and primary tumor location on the head or neck.
Patients with negative single lymph node biopsy (SLNB) were less likely to have recurrence than were those who did not undergo SLNB. Among 64 patients whose locoregional disease was excised, 37 (57.8%) were disease free at 2 years, whereas 7 patients (10.9%) had new locoregional disease and 20 patients (31.3%) developed a new distant recurrence.
“[O]ur data appear to support the recommendation for careful scar and regional skin and lymph node examination during patient follow-up,” the investigators concluded, alluding to the relatively high rate of locoregional recurrence. “Subsequent recurrences occurring at distant sites were more likely to involve multiple organs, which is consistent with other studies.”
The second melanoma article, investigating associations between time to relapse and survival, was authored by Anaïs Vallet, MD, of Hôpital Saint-Louis, Paris, and colleagues.
“Although the kinetics of metastatic disease seem to be correlated with patient survival, the first relapse is not predictable, and data from the literature on the topic are controversial,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0425). “We hypothesized that the progression of the metastatic disease would be associated with the time from primary excision to the first distant recurrence of melanoma.”
To test this hypothesis, the investigators analyzed data from 638 patients with unresectable stage III or IV melanoma. Inclusion required first-line treatment with chemotherapy, targeted therapies, or immunotherapies. The interval between primary excision and distant disease recurrence, measured as a categorical and continuous variable, was compared with overall survival and progression-free survival. The analysis revealed no associations between time to recurrence and either survival measure, even when stratified by treatment.
“Now that immunotherapies and targeted therapies have been approved in the adjuvant setting for patients with stage III disease, it would be interesting to analyze recurrence-free survival and [progression-free survival] in relapsing patients who previously received adjuvant therapies,” the investigators wrote.
The third study was conducted by Laura Calomarde-Rees, MD, of Instituto Valenciano de Oncología, València, Spain, and colleagues.
“Our aim was to identify risk factors associated with lymphatic (locoregional metastasis) or hematogenous (distant metastasis) progression because these have not been studied separately to date in patients with localized melanoma,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0069).
The retrospective study involved 1,177 patients with stage I to II melanoma. Multiple disease variables were evaluated in the context of each type of metastasis, including age, sex, tumor location, and others.
The investigators found locoregional spread was most often associated with vascular invasion (hazard ratio [HR], 3.2), greater Breslow thickness (HR, 5.4; thickness greater than 4 mm), acral location (HR, 2.4), head/neck location (HR, 1.7), and age greater than 55 years (HR, 1.9).
Distant metastasis was most often associated with greater Breslow thickness (HR, 10.4; thickness greater than 4 mm), TERT promoter mutations (HR, 2.9), BRAF mutations (HR, 1.9), and absence of regression (HR, 0.1).
“Risk factors for lymphatic and hematogenous metastasis differ,” the investigators concluded. “A greater understanding of the clinical, histopathologic, and molecular factors involved could help to identify patients with an increased risk of recurrence and guide the design of individualized follow-up programs and adjuvant targeted therapies.”
Dr. von Schuckmann and colleagues disclosed study funding from the National Health and Medical Research Council and other relationships with the Norwegian Cancer Society project. Dr. Vallet and colleagues reported study support from French National Cancer Institute, MSD, BMS, Roche, and Novartis; and additional relationships with Incyte, Amgen, Pfizer, and others. Dr. Calomarde-Rees and colleagues disclosed no conflicts of interest.
As systemic therapies for advanced melanoma increase, some historical prognostic factors continue to hold true while refined and novel risk factors are emerging, according to the results of three studies published in JAMA Dermatology.
Among the most prominent findings of those studies are that ulceration, mitotic index, and head and neck location in localized disease were predictive of early recurrence; time to recurrence was not associated with survival in unresectable stage IV melanoma; and certain gene markers may be linked with particular types of metastasis.
The first study, conducted by Lena A. von Schuckmann, MBBS, of the University of Queensland School of Public Health in Australia, and colleagues, evaluated the risk of early melanoma recurrence in patients with localized disease.
“With the introduction of targeted and immune therapies for treatment of metastatic melanoma, including possible adjuvant therapy, a detailed understanding of the risk of melanoma recurrence may assist clinicians to advise patients with a primary tumor at high risk of disease metastasis,” the researchers wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0440).
They conducted a prospective cohort study of 700 patients with high-risk, category T1b to T4b cutaneous melanoma, refined from an initial recruitment population of 1,254 individuals. Using self-administered patient questionnaires in conjunction with histologic, imaging, and clinical data over the course of 2 years, the investigators looked for factors that predicted recurrence.
Of 700 patients, 94 (13.4%) had disease recurrence, most often (70.2%) locoregional recurrence. Independent predictors of recurrence included mitotic rate greater than 3/mm2, thickness, ulceration, and primary tumor location on the head or neck.
Patients with negative single lymph node biopsy (SLNB) were less likely to have recurrence than were those who did not undergo SLNB. Among 64 patients whose locoregional disease was excised, 37 (57.8%) were disease free at 2 years, whereas 7 patients (10.9%) had new locoregional disease and 20 patients (31.3%) developed a new distant recurrence.
“[O]ur data appear to support the recommendation for careful scar and regional skin and lymph node examination during patient follow-up,” the investigators concluded, alluding to the relatively high rate of locoregional recurrence. “Subsequent recurrences occurring at distant sites were more likely to involve multiple organs, which is consistent with other studies.”
The second melanoma article, investigating associations between time to relapse and survival, was authored by Anaïs Vallet, MD, of Hôpital Saint-Louis, Paris, and colleagues.
“Although the kinetics of metastatic disease seem to be correlated with patient survival, the first relapse is not predictable, and data from the literature on the topic are controversial,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0425). “We hypothesized that the progression of the metastatic disease would be associated with the time from primary excision to the first distant recurrence of melanoma.”
To test this hypothesis, the investigators analyzed data from 638 patients with unresectable stage III or IV melanoma. Inclusion required first-line treatment with chemotherapy, targeted therapies, or immunotherapies. The interval between primary excision and distant disease recurrence, measured as a categorical and continuous variable, was compared with overall survival and progression-free survival. The analysis revealed no associations between time to recurrence and either survival measure, even when stratified by treatment.
“Now that immunotherapies and targeted therapies have been approved in the adjuvant setting for patients with stage III disease, it would be interesting to analyze recurrence-free survival and [progression-free survival] in relapsing patients who previously received adjuvant therapies,” the investigators wrote.
The third study was conducted by Laura Calomarde-Rees, MD, of Instituto Valenciano de Oncología, València, Spain, and colleagues.
“Our aim was to identify risk factors associated with lymphatic (locoregional metastasis) or hematogenous (distant metastasis) progression because these have not been studied separately to date in patients with localized melanoma,” they wrote (JAMA Dermatol. 2019 May 1. doi: 10.1001/jamadermatol.2019.0069).
The retrospective study involved 1,177 patients with stage I to II melanoma. Multiple disease variables were evaluated in the context of each type of metastasis, including age, sex, tumor location, and others.
The investigators found locoregional spread was most often associated with vascular invasion (hazard ratio [HR], 3.2), greater Breslow thickness (HR, 5.4; thickness greater than 4 mm), acral location (HR, 2.4), head/neck location (HR, 1.7), and age greater than 55 years (HR, 1.9).
Distant metastasis was most often associated with greater Breslow thickness (HR, 10.4; thickness greater than 4 mm), TERT promoter mutations (HR, 2.9), BRAF mutations (HR, 1.9), and absence of regression (HR, 0.1).
“Risk factors for lymphatic and hematogenous metastasis differ,” the investigators concluded. “A greater understanding of the clinical, histopathologic, and molecular factors involved could help to identify patients with an increased risk of recurrence and guide the design of individualized follow-up programs and adjuvant targeted therapies.”
Dr. von Schuckmann and colleagues disclosed study funding from the National Health and Medical Research Council and other relationships with the Norwegian Cancer Society project. Dr. Vallet and colleagues reported study support from French National Cancer Institute, MSD, BMS, Roche, and Novartis; and additional relationships with Incyte, Amgen, Pfizer, and others. Dr. Calomarde-Rees and colleagues disclosed no conflicts of interest.
FROM JAMA DERMATOLOGY
CMS proposes payment increase for administering CAR T in the hospital
Hospitals could get a payment bump for administering chimeric antigen receptor (CAR) T-cell therapies under a proposed rule issued by the Centers for Medicare & Medicaid Services.
The proposal calls for raising the new technology add-on payment (NTAP) associated with the therapies from 50% of the technology to 65%, an increase from $186,500 to $242,450.
Beginning with discharges on Oct. 1, 2019, if discharge costs involving a new medical service or technology exceed the full Medicare Severity Diagnosis-Related Group (DRG) payment, Medicare would make an add-on payment of either 65% of the cost of the new medical service or technology, or 65% of the amount by which the costs of the case exceed the standard DRG payment, whichever is less.
Roy Silverstein, MD, president of the American Society of Hematology, said the group was pleased that the CMS is examining its existing payment policies to identify more realistic ways to account for the costs of administering CAR T-cell therapies.
“While ASH had originally suggested a higher [new technology] payment, any increase is an improvement,” Dr. Silverstein said in a statement. “While the proposal from CMS is promising, it is not a one-stop solution for making CAR T more accessible to patients. Just as these therapies are innovative, it is going to take some innovation on the part of CMS to develop a plan that equitably compensates providers and institutions so that offering the therapy is sustainable.”
The agency’s proposal follows an August 2018 final rule by the CMS that set a new payment scheme for inpatient administration of two CAR T-cell therapies. The rule categorized CAR T-cell therapies under the umbrella of the renamed Medicare Severity–Diagnosis Related Groups (MS-DRG) 016 – Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy – and assigned ICD-10 PCS procedure codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) in the inpatient setting for fiscal year 2019, which began in October 2018.
In April 2018, the CMS announced payment rates for outpatient administration of the two drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.
In February 2019, the CMS also proposed to cover CAR T-cell therapy for cancer patients participating in clinical trials that study the treatment’s effectiveness. A final decision on the proposal is expected in May 2019.
In the current proposal, the CMS acknowledged requests calling for the agency to create a new MS-DRG for procedures involving CAR T-cell therapies to improve payment in the inpatient setting. However, the agency declined to create a new MS-DRG for CAR T-cell cases, writing that the move is premature given the relative newness of CAR T-cell therapy and the agency’s proposal to continue new technology add-on payments for fiscal 2020 for Kymriah and Yescarta.
However, the agency is requesting public comments on whether, in light of additional experience with billing and payment for cases involving CAR T-cell therapies to Medicare patients, the CMS should consider using a specific cost-to-charge ratio for ICD-10-PCS procedure codes used to report the performance of procedures involving CAR T-cell therapies.
Comments on the proposed rule will be accepted until June 24.
Hospitals could get a payment bump for administering chimeric antigen receptor (CAR) T-cell therapies under a proposed rule issued by the Centers for Medicare & Medicaid Services.
The proposal calls for raising the new technology add-on payment (NTAP) associated with the therapies from 50% of the technology to 65%, an increase from $186,500 to $242,450.
Beginning with discharges on Oct. 1, 2019, if discharge costs involving a new medical service or technology exceed the full Medicare Severity Diagnosis-Related Group (DRG) payment, Medicare would make an add-on payment of either 65% of the cost of the new medical service or technology, or 65% of the amount by which the costs of the case exceed the standard DRG payment, whichever is less.
Roy Silverstein, MD, president of the American Society of Hematology, said the group was pleased that the CMS is examining its existing payment policies to identify more realistic ways to account for the costs of administering CAR T-cell therapies.
“While ASH had originally suggested a higher [new technology] payment, any increase is an improvement,” Dr. Silverstein said in a statement. “While the proposal from CMS is promising, it is not a one-stop solution for making CAR T more accessible to patients. Just as these therapies are innovative, it is going to take some innovation on the part of CMS to develop a plan that equitably compensates providers and institutions so that offering the therapy is sustainable.”
The agency’s proposal follows an August 2018 final rule by the CMS that set a new payment scheme for inpatient administration of two CAR T-cell therapies. The rule categorized CAR T-cell therapies under the umbrella of the renamed Medicare Severity–Diagnosis Related Groups (MS-DRG) 016 – Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy – and assigned ICD-10 PCS procedure codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) in the inpatient setting for fiscal year 2019, which began in October 2018.
In April 2018, the CMS announced payment rates for outpatient administration of the two drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.
In February 2019, the CMS also proposed to cover CAR T-cell therapy for cancer patients participating in clinical trials that study the treatment’s effectiveness. A final decision on the proposal is expected in May 2019.
In the current proposal, the CMS acknowledged requests calling for the agency to create a new MS-DRG for procedures involving CAR T-cell therapies to improve payment in the inpatient setting. However, the agency declined to create a new MS-DRG for CAR T-cell cases, writing that the move is premature given the relative newness of CAR T-cell therapy and the agency’s proposal to continue new technology add-on payments for fiscal 2020 for Kymriah and Yescarta.
However, the agency is requesting public comments on whether, in light of additional experience with billing and payment for cases involving CAR T-cell therapies to Medicare patients, the CMS should consider using a specific cost-to-charge ratio for ICD-10-PCS procedure codes used to report the performance of procedures involving CAR T-cell therapies.
Comments on the proposed rule will be accepted until June 24.
Hospitals could get a payment bump for administering chimeric antigen receptor (CAR) T-cell therapies under a proposed rule issued by the Centers for Medicare & Medicaid Services.
The proposal calls for raising the new technology add-on payment (NTAP) associated with the therapies from 50% of the technology to 65%, an increase from $186,500 to $242,450.
Beginning with discharges on Oct. 1, 2019, if discharge costs involving a new medical service or technology exceed the full Medicare Severity Diagnosis-Related Group (DRG) payment, Medicare would make an add-on payment of either 65% of the cost of the new medical service or technology, or 65% of the amount by which the costs of the case exceed the standard DRG payment, whichever is less.
Roy Silverstein, MD, president of the American Society of Hematology, said the group was pleased that the CMS is examining its existing payment policies to identify more realistic ways to account for the costs of administering CAR T-cell therapies.
“While ASH had originally suggested a higher [new technology] payment, any increase is an improvement,” Dr. Silverstein said in a statement. “While the proposal from CMS is promising, it is not a one-stop solution for making CAR T more accessible to patients. Just as these therapies are innovative, it is going to take some innovation on the part of CMS to develop a plan that equitably compensates providers and institutions so that offering the therapy is sustainable.”
The agency’s proposal follows an August 2018 final rule by the CMS that set a new payment scheme for inpatient administration of two CAR T-cell therapies. The rule categorized CAR T-cell therapies under the umbrella of the renamed Medicare Severity–Diagnosis Related Groups (MS-DRG) 016 – Autologous Bone Marrow Transplant with CC/MCC or T-cell Immunotherapy – and assigned ICD-10 PCS procedure codes XW033C3 and XW043C3 to the use of axicabtagene ciloleucel (Yescarta) and tisagenlecleucel (Kymriah) in the inpatient setting for fiscal year 2019, which began in October 2018.
In April 2018, the CMS announced payment rates for outpatient administration of the two drugs, settling on $395,380 for axicabtagene ciloleucel and $500,839 for tisagenlecleucel. The two medications have list prices of $373,000 and $475,000, respectively.
In February 2019, the CMS also proposed to cover CAR T-cell therapy for cancer patients participating in clinical trials that study the treatment’s effectiveness. A final decision on the proposal is expected in May 2019.
In the current proposal, the CMS acknowledged requests calling for the agency to create a new MS-DRG for procedures involving CAR T-cell therapies to improve payment in the inpatient setting. However, the agency declined to create a new MS-DRG for CAR T-cell cases, writing that the move is premature given the relative newness of CAR T-cell therapy and the agency’s proposal to continue new technology add-on payments for fiscal 2020 for Kymriah and Yescarta.
However, the agency is requesting public comments on whether, in light of additional experience with billing and payment for cases involving CAR T-cell therapies to Medicare patients, the CMS should consider using a specific cost-to-charge ratio for ICD-10-PCS procedure codes used to report the performance of procedures involving CAR T-cell therapies.
Comments on the proposed rule will be accepted until June 24.
Trump administration asks court to invalidate ACA
The Trump administration is asking an appeals court to strike down the entire Affordable Care Act (ACA), a shift from the administration’s earlier stance that had supported some elements of the law in a lawsuit challenging its constitutionality.
In a brief issued May 1 to the 5th U.S. Court of Appeals, Justice Department attorneys wrote that provisions of the health care law cannot be severed from the whole and thus, the entire ACA should be ruled invalid. The Justice Department did not specify why it changed its position in Texas v. United States, except to say the new opinion came upon further consideration and review of the lower court’s opinion.
Texas v. United States, filed by a group of 18 Republican state attorneys general and two individuals in 2018, centers on whether the ACA should stand if provisions of the law are no longer valid. The plaintiffs argue that, because budget legislation in 2017 zeroed out the penalties associated with the ACA’s individual mandate, the mandate is invalid. If the mandate is severed, the entire ACA should be struck down, the plaintiffs said. The Justice Department declined to fully defend the law and so 16 Democratic state attorneys general intervened to defend the ACA in the case.
In an initial brief, the Trump administration agreed that the mandate was unconstitutional and should be parsed. Attorneys for the administration wrote that, if the mandate is found unconstitutional, the court should also consider finding two other provisions – the guaranteed issue and community rating requirements – of the ACA invalid. Guaranteed issue refers to insurers in the individual market offering coverage to all citizens, regardless of preexisting conditions, while community rating refers to charging equal premiums to every patient, no matter their past health status. At the time however, the Trump administration said the remainder of the ACA can stand without the three linked provisions.
In December 2018, a district court declared the entire ACA to be invalid, a decision immediately appealed to the 5th Circuit by the Democratic attorneys general. The circuit court froze the case in light of the federal government’s partial shutdown at the time. The case remains on hold.
The Trump administration’s new stance that the entire ACA should be declared unconstitutional was widely condemned by Democratic legislators.
“If President Trump wins against health care, families lose,” Sen. Patty Murray (D-Wash.) tweeted May 1. “They’ll lose their health care, lose protections for preexisting conditions, and lose to insurance companies who will have free rein to deny coverage and leave patients to shoulder high costs.”
The White House had not issued a statement about its new position in the case at press time.
In a separate brief filed with the appeals court on May 1, Texas Attorney General Ken Paxton, a Republican plaintiff in the case, reiterated his side’s opposition to the ACA and called for the court to uphold the lower court’s ruling striking down the law.
“Congress meant for the individual mandate to be the centerpiece of Obamacare,” Attorney General Paxton said in a statement. “Without the constitutional justification for the centerpiece, the law must go down. Obamacare is a failed social experiment. The sooner it is invalidated, the better, so each state can decide what type of health care system it wants and how best to provide for those with preexisting conditions, which is federalism that the founders intended.”
Timothy Jost, a health law professor at Washington and Lee University in Lexington, Va., said that administration’s revised position in Texas v. U.S. won’t have much impact on the case.
“The Department of Justice brief doesn’t change anything,” Mr. Jost said in an interview. “They basically make the same arguments that the individual plaintiffs and the state plaintiffs do as to the major issues in the case.
However, Mr. Jost said that the administration’s brief sounds confused and reads almost like two separate briefs. On one hand, the Justice Department argues that the entire ACA should be invalid because the mandate cannot be severed. On the other hand, the agency argues that court relief should be “limited only to those provisions that actually injure the individual plaintiffs.” Specifically, Justice Department attorneys indicate that health care fraud and abuse protections in the ACA should be preserved.
“It looks like they kind of want to have their cake and eat it, too,” Mr. Jost said. “They want to preserve the provisions of the ACA they like, but not the sections that they don’t like. That could serve to confuse the issue for the appellate court.”
Oral arguments in the case are slated for July with a possible decision expected by the end of 2019. Legal analysts expect the losing side to appeal to the Supreme Court.
The Trump administration is asking an appeals court to strike down the entire Affordable Care Act (ACA), a shift from the administration’s earlier stance that had supported some elements of the law in a lawsuit challenging its constitutionality.
In a brief issued May 1 to the 5th U.S. Court of Appeals, Justice Department attorneys wrote that provisions of the health care law cannot be severed from the whole and thus, the entire ACA should be ruled invalid. The Justice Department did not specify why it changed its position in Texas v. United States, except to say the new opinion came upon further consideration and review of the lower court’s opinion.
Texas v. United States, filed by a group of 18 Republican state attorneys general and two individuals in 2018, centers on whether the ACA should stand if provisions of the law are no longer valid. The plaintiffs argue that, because budget legislation in 2017 zeroed out the penalties associated with the ACA’s individual mandate, the mandate is invalid. If the mandate is severed, the entire ACA should be struck down, the plaintiffs said. The Justice Department declined to fully defend the law and so 16 Democratic state attorneys general intervened to defend the ACA in the case.
In an initial brief, the Trump administration agreed that the mandate was unconstitutional and should be parsed. Attorneys for the administration wrote that, if the mandate is found unconstitutional, the court should also consider finding two other provisions – the guaranteed issue and community rating requirements – of the ACA invalid. Guaranteed issue refers to insurers in the individual market offering coverage to all citizens, regardless of preexisting conditions, while community rating refers to charging equal premiums to every patient, no matter their past health status. At the time however, the Trump administration said the remainder of the ACA can stand without the three linked provisions.
In December 2018, a district court declared the entire ACA to be invalid, a decision immediately appealed to the 5th Circuit by the Democratic attorneys general. The circuit court froze the case in light of the federal government’s partial shutdown at the time. The case remains on hold.
The Trump administration’s new stance that the entire ACA should be declared unconstitutional was widely condemned by Democratic legislators.
“If President Trump wins against health care, families lose,” Sen. Patty Murray (D-Wash.) tweeted May 1. “They’ll lose their health care, lose protections for preexisting conditions, and lose to insurance companies who will have free rein to deny coverage and leave patients to shoulder high costs.”
The White House had not issued a statement about its new position in the case at press time.
In a separate brief filed with the appeals court on May 1, Texas Attorney General Ken Paxton, a Republican plaintiff in the case, reiterated his side’s opposition to the ACA and called for the court to uphold the lower court’s ruling striking down the law.
“Congress meant for the individual mandate to be the centerpiece of Obamacare,” Attorney General Paxton said in a statement. “Without the constitutional justification for the centerpiece, the law must go down. Obamacare is a failed social experiment. The sooner it is invalidated, the better, so each state can decide what type of health care system it wants and how best to provide for those with preexisting conditions, which is federalism that the founders intended.”
Timothy Jost, a health law professor at Washington and Lee University in Lexington, Va., said that administration’s revised position in Texas v. U.S. won’t have much impact on the case.
“The Department of Justice brief doesn’t change anything,” Mr. Jost said in an interview. “They basically make the same arguments that the individual plaintiffs and the state plaintiffs do as to the major issues in the case.
However, Mr. Jost said that the administration’s brief sounds confused and reads almost like two separate briefs. On one hand, the Justice Department argues that the entire ACA should be invalid because the mandate cannot be severed. On the other hand, the agency argues that court relief should be “limited only to those provisions that actually injure the individual plaintiffs.” Specifically, Justice Department attorneys indicate that health care fraud and abuse protections in the ACA should be preserved.
“It looks like they kind of want to have their cake and eat it, too,” Mr. Jost said. “They want to preserve the provisions of the ACA they like, but not the sections that they don’t like. That could serve to confuse the issue for the appellate court.”
Oral arguments in the case are slated for July with a possible decision expected by the end of 2019. Legal analysts expect the losing side to appeal to the Supreme Court.
The Trump administration is asking an appeals court to strike down the entire Affordable Care Act (ACA), a shift from the administration’s earlier stance that had supported some elements of the law in a lawsuit challenging its constitutionality.
In a brief issued May 1 to the 5th U.S. Court of Appeals, Justice Department attorneys wrote that provisions of the health care law cannot be severed from the whole and thus, the entire ACA should be ruled invalid. The Justice Department did not specify why it changed its position in Texas v. United States, except to say the new opinion came upon further consideration and review of the lower court’s opinion.
Texas v. United States, filed by a group of 18 Republican state attorneys general and two individuals in 2018, centers on whether the ACA should stand if provisions of the law are no longer valid. The plaintiffs argue that, because budget legislation in 2017 zeroed out the penalties associated with the ACA’s individual mandate, the mandate is invalid. If the mandate is severed, the entire ACA should be struck down, the plaintiffs said. The Justice Department declined to fully defend the law and so 16 Democratic state attorneys general intervened to defend the ACA in the case.
In an initial brief, the Trump administration agreed that the mandate was unconstitutional and should be parsed. Attorneys for the administration wrote that, if the mandate is found unconstitutional, the court should also consider finding two other provisions – the guaranteed issue and community rating requirements – of the ACA invalid. Guaranteed issue refers to insurers in the individual market offering coverage to all citizens, regardless of preexisting conditions, while community rating refers to charging equal premiums to every patient, no matter their past health status. At the time however, the Trump administration said the remainder of the ACA can stand without the three linked provisions.
In December 2018, a district court declared the entire ACA to be invalid, a decision immediately appealed to the 5th Circuit by the Democratic attorneys general. The circuit court froze the case in light of the federal government’s partial shutdown at the time. The case remains on hold.
The Trump administration’s new stance that the entire ACA should be declared unconstitutional was widely condemned by Democratic legislators.
“If President Trump wins against health care, families lose,” Sen. Patty Murray (D-Wash.) tweeted May 1. “They’ll lose their health care, lose protections for preexisting conditions, and lose to insurance companies who will have free rein to deny coverage and leave patients to shoulder high costs.”
The White House had not issued a statement about its new position in the case at press time.
In a separate brief filed with the appeals court on May 1, Texas Attorney General Ken Paxton, a Republican plaintiff in the case, reiterated his side’s opposition to the ACA and called for the court to uphold the lower court’s ruling striking down the law.
“Congress meant for the individual mandate to be the centerpiece of Obamacare,” Attorney General Paxton said in a statement. “Without the constitutional justification for the centerpiece, the law must go down. Obamacare is a failed social experiment. The sooner it is invalidated, the better, so each state can decide what type of health care system it wants and how best to provide for those with preexisting conditions, which is federalism that the founders intended.”
Timothy Jost, a health law professor at Washington and Lee University in Lexington, Va., said that administration’s revised position in Texas v. U.S. won’t have much impact on the case.
“The Department of Justice brief doesn’t change anything,” Mr. Jost said in an interview. “They basically make the same arguments that the individual plaintiffs and the state plaintiffs do as to the major issues in the case.
However, Mr. Jost said that the administration’s brief sounds confused and reads almost like two separate briefs. On one hand, the Justice Department argues that the entire ACA should be invalid because the mandate cannot be severed. On the other hand, the agency argues that court relief should be “limited only to those provisions that actually injure the individual plaintiffs.” Specifically, Justice Department attorneys indicate that health care fraud and abuse protections in the ACA should be preserved.
“It looks like they kind of want to have their cake and eat it, too,” Mr. Jost said. “They want to preserve the provisions of the ACA they like, but not the sections that they don’t like. That could serve to confuse the issue for the appellate court.”
Oral arguments in the case are slated for July with a possible decision expected by the end of 2019. Legal analysts expect the losing side to appeal to the Supreme Court.
Opioid management program reduced number of narcotics prescribed after breast surgery
An opioid prescription management program implemented at the Cleveland Clinic has led to a reduction in the number of narcotics prescribed to patients after breast surgery, according to research presented in a recent webcast from the annual meeting of the American Society of Breast Surgeons.
“The opioid epidemic has become a critical issue, and narcotic abuse has continued to rise,” Stephanie Valente, DO, FACS, from the Cleveland Clinic, said in her presentation. “Excess narcotic prescriptions may be contributing to this opioid epidemic,” and there are no current narcotic prescribing guidelines for patients after breast surgery, she said. In addition, studies have shown surgeons can overestimate the number of opioid pills a patient needs after surgery for pain control, and any excess pills are at risk of being stolen or inappropriately used, she added.
Dr. Valente and colleagues performed a baseline evaluation of narcotic pills prescribed by surgeons at the Cleveland Clinic for patients who have undergone excisional biopsy or lumpectomy, mastectomy, and mastectomy with reconstruction. They found the median number of narcotics prescribed were 15 pills for excisional biopsy or lumpectomy patients, 20 pills for mastectomy patients and 28 pills for mastectomy with reconstruction patients.
The researchers sought to lower those numbers, and created a departmental change in which they decreased the median number of pills prescribed at discharge from 15 pills to 10 pills for excisional biopsy or lumpectomy patients and from 28 pills to 25 pills for patients who undergo mastectomy with reconstruction. They then examined 100 consecutive patients after a 3-month implementation period to determine whether prescribing numbers had changed and found the surgeons adhered to the prescribing guidelines, which resulted in a statistically significant reduction in median opioid pills prescribed for excisional biopsy or lumpectomy (P less than .01) and mastectomy with reconstruction patients (P less than .01).
“After their departmental plan change, we observed that, as planned, a statistically significant decrease in prescribing practices amongst surgeons was able to be performed, showing that surgeons were able to adhere to these new prescribing practices,” said Dr. Valente.
When they examined the number of pills patients reported they used after surgery, they found excisional biopsy or lumpectomy patients took an average of 1 pill, mastectomy patients took an average of 3 pills, and mastectomy with reconstruction patients took an average of 18 pills. “These were all statistically much less than what was being prescribed even after our purposeful reduction,” said Dr. Valente.
In the study, 40% of patients who underwent breast surgery overall reported that they did not have any postoperative narcotic use at all, with the least narcotic use seen among patients who underwent excisional biopsy or lumpectomy.
“Further directions for opiate reduction can include evaluation of the impact of type and amount of local anesthetic given intraoperatively, and the amount of narcotics used postoperatively … to identify patient factors that contribute to the low narcotic usage postoperatively, and finally, to figure out how to maximize the benefit of adding a formal ERAS [enhanced recovery after surgery] protocol to further reduce patient needs for as many narcotic pills,” said Dr. Valente.
Dr. Valente had no disclosures.
An opioid prescription management program implemented at the Cleveland Clinic has led to a reduction in the number of narcotics prescribed to patients after breast surgery, according to research presented in a recent webcast from the annual meeting of the American Society of Breast Surgeons.
“The opioid epidemic has become a critical issue, and narcotic abuse has continued to rise,” Stephanie Valente, DO, FACS, from the Cleveland Clinic, said in her presentation. “Excess narcotic prescriptions may be contributing to this opioid epidemic,” and there are no current narcotic prescribing guidelines for patients after breast surgery, she said. In addition, studies have shown surgeons can overestimate the number of opioid pills a patient needs after surgery for pain control, and any excess pills are at risk of being stolen or inappropriately used, she added.
Dr. Valente and colleagues performed a baseline evaluation of narcotic pills prescribed by surgeons at the Cleveland Clinic for patients who have undergone excisional biopsy or lumpectomy, mastectomy, and mastectomy with reconstruction. They found the median number of narcotics prescribed were 15 pills for excisional biopsy or lumpectomy patients, 20 pills for mastectomy patients and 28 pills for mastectomy with reconstruction patients.
The researchers sought to lower those numbers, and created a departmental change in which they decreased the median number of pills prescribed at discharge from 15 pills to 10 pills for excisional biopsy or lumpectomy patients and from 28 pills to 25 pills for patients who undergo mastectomy with reconstruction. They then examined 100 consecutive patients after a 3-month implementation period to determine whether prescribing numbers had changed and found the surgeons adhered to the prescribing guidelines, which resulted in a statistically significant reduction in median opioid pills prescribed for excisional biopsy or lumpectomy (P less than .01) and mastectomy with reconstruction patients (P less than .01).
“After their departmental plan change, we observed that, as planned, a statistically significant decrease in prescribing practices amongst surgeons was able to be performed, showing that surgeons were able to adhere to these new prescribing practices,” said Dr. Valente.
When they examined the number of pills patients reported they used after surgery, they found excisional biopsy or lumpectomy patients took an average of 1 pill, mastectomy patients took an average of 3 pills, and mastectomy with reconstruction patients took an average of 18 pills. “These were all statistically much less than what was being prescribed even after our purposeful reduction,” said Dr. Valente.
In the study, 40% of patients who underwent breast surgery overall reported that they did not have any postoperative narcotic use at all, with the least narcotic use seen among patients who underwent excisional biopsy or lumpectomy.
“Further directions for opiate reduction can include evaluation of the impact of type and amount of local anesthetic given intraoperatively, and the amount of narcotics used postoperatively … to identify patient factors that contribute to the low narcotic usage postoperatively, and finally, to figure out how to maximize the benefit of adding a formal ERAS [enhanced recovery after surgery] protocol to further reduce patient needs for as many narcotic pills,” said Dr. Valente.
Dr. Valente had no disclosures.
An opioid prescription management program implemented at the Cleveland Clinic has led to a reduction in the number of narcotics prescribed to patients after breast surgery, according to research presented in a recent webcast from the annual meeting of the American Society of Breast Surgeons.
“The opioid epidemic has become a critical issue, and narcotic abuse has continued to rise,” Stephanie Valente, DO, FACS, from the Cleveland Clinic, said in her presentation. “Excess narcotic prescriptions may be contributing to this opioid epidemic,” and there are no current narcotic prescribing guidelines for patients after breast surgery, she said. In addition, studies have shown surgeons can overestimate the number of opioid pills a patient needs after surgery for pain control, and any excess pills are at risk of being stolen or inappropriately used, she added.
Dr. Valente and colleagues performed a baseline evaluation of narcotic pills prescribed by surgeons at the Cleveland Clinic for patients who have undergone excisional biopsy or lumpectomy, mastectomy, and mastectomy with reconstruction. They found the median number of narcotics prescribed were 15 pills for excisional biopsy or lumpectomy patients, 20 pills for mastectomy patients and 28 pills for mastectomy with reconstruction patients.
The researchers sought to lower those numbers, and created a departmental change in which they decreased the median number of pills prescribed at discharge from 15 pills to 10 pills for excisional biopsy or lumpectomy patients and from 28 pills to 25 pills for patients who undergo mastectomy with reconstruction. They then examined 100 consecutive patients after a 3-month implementation period to determine whether prescribing numbers had changed and found the surgeons adhered to the prescribing guidelines, which resulted in a statistically significant reduction in median opioid pills prescribed for excisional biopsy or lumpectomy (P less than .01) and mastectomy with reconstruction patients (P less than .01).
“After their departmental plan change, we observed that, as planned, a statistically significant decrease in prescribing practices amongst surgeons was able to be performed, showing that surgeons were able to adhere to these new prescribing practices,” said Dr. Valente.
When they examined the number of pills patients reported they used after surgery, they found excisional biopsy or lumpectomy patients took an average of 1 pill, mastectomy patients took an average of 3 pills, and mastectomy with reconstruction patients took an average of 18 pills. “These were all statistically much less than what was being prescribed even after our purposeful reduction,” said Dr. Valente.
In the study, 40% of patients who underwent breast surgery overall reported that they did not have any postoperative narcotic use at all, with the least narcotic use seen among patients who underwent excisional biopsy or lumpectomy.
“Further directions for opiate reduction can include evaluation of the impact of type and amount of local anesthetic given intraoperatively, and the amount of narcotics used postoperatively … to identify patient factors that contribute to the low narcotic usage postoperatively, and finally, to figure out how to maximize the benefit of adding a formal ERAS [enhanced recovery after surgery] protocol to further reduce patient needs for as many narcotic pills,” said Dr. Valente.
Dr. Valente had no disclosures.
REPORTING FROM ASBS 2019
HHS finalizes controversial conscience regulation
Health care professionals may not be compelled to provide medical care, including abortion services or even referrals, if they object on religious or moral grounds under a federal regulation finalized May 2.
The regulation also requires health care entities that receive federal funding to alert their employees to their federal conscience rights.
This final rule “replaces a 2011 rule that has proven inadequate, and ensures that HHS implements the full set of tools appropriate for enforcing the conscience protections passed by Congress,” HHS officials said in a statement. “These federal laws protect providers, individuals, and other health care entities from having to provide, participate in, pay for, provide coverage of, or refer for, services such as abortion, sterilization, or assisted suicide. It also includes conscience protections with respect to advance directives.”
The regulation was first proposed in January 2018, shortly after the formation of the Conscience and Religious Freedom Division within the HHS Office of Civil Rights (OCR).
Application of the regulation extends beyond the clinic and hospital. The regulation notes that, on a case-by-case basis, those providing emergency services such as EMTs or even ambulance drivers could be protected should they choose to exercise their conscience and not provide services based on their religious beliefs.
“With this final rule, the Department seeks to educate protected entities and covered entities as to their legal rights and obligations; to encourage individuals and organizations with religious beliefs or moral convictions to enter, or remain in, the health care industry; and to prevent others from being dissuaded from filing complaints due to prior OCR complaint resolutions or sub-regulatory guidance that no reflect the views of the Department,” according to the regulation.
HHS officials denied accusations that the regulation puts the needs of providers over those of patients.
By “protecting a diversity of beliefs among health care providers, these protections ensure that options are available to patients who desire, and would feel most comfortable with, a provider whose religious beliefs or moral convictions match their own. Even where a patient and provider do not share the same religious beliefs or moral convictions, it is not necessarily the case that patients would want providers to be forced to violate their religious beliefs or moral convictions,” according to the regulation.
However, the American Civil Liberties Union and others see the new regulation as license to discriminate.
“Once again, this administration shows itself to be determined to use religious liberty to harm communities it deems less worthy of equal treatment under the law,” Louise Melling, ACLU deputy legal director, said in a statement. “This rule threatens to prevent people from accessing critical medical care and may endanger people’s lives. Religious liberty is a fundamental right, but it does not include the right to discriminate or harm others. Denying patients health care is not religious liberty. Discriminating against patients based on their gender or gender expression is not religious liberty. Medical standards, not religious beliefs, should guide medical care.”
The regulation does not yet have a scheduled publication date in the Federal Register, nor has it been posted as a preview document on the publication’s website. It will become effective 60 days after publication.
Health care professionals may not be compelled to provide medical care, including abortion services or even referrals, if they object on religious or moral grounds under a federal regulation finalized May 2.
The regulation also requires health care entities that receive federal funding to alert their employees to their federal conscience rights.
This final rule “replaces a 2011 rule that has proven inadequate, and ensures that HHS implements the full set of tools appropriate for enforcing the conscience protections passed by Congress,” HHS officials said in a statement. “These federal laws protect providers, individuals, and other health care entities from having to provide, participate in, pay for, provide coverage of, or refer for, services such as abortion, sterilization, or assisted suicide. It also includes conscience protections with respect to advance directives.”
The regulation was first proposed in January 2018, shortly after the formation of the Conscience and Religious Freedom Division within the HHS Office of Civil Rights (OCR).
Application of the regulation extends beyond the clinic and hospital. The regulation notes that, on a case-by-case basis, those providing emergency services such as EMTs or even ambulance drivers could be protected should they choose to exercise their conscience and not provide services based on their religious beliefs.
“With this final rule, the Department seeks to educate protected entities and covered entities as to their legal rights and obligations; to encourage individuals and organizations with religious beliefs or moral convictions to enter, or remain in, the health care industry; and to prevent others from being dissuaded from filing complaints due to prior OCR complaint resolutions or sub-regulatory guidance that no reflect the views of the Department,” according to the regulation.
HHS officials denied accusations that the regulation puts the needs of providers over those of patients.
By “protecting a diversity of beliefs among health care providers, these protections ensure that options are available to patients who desire, and would feel most comfortable with, a provider whose religious beliefs or moral convictions match their own. Even where a patient and provider do not share the same religious beliefs or moral convictions, it is not necessarily the case that patients would want providers to be forced to violate their religious beliefs or moral convictions,” according to the regulation.
However, the American Civil Liberties Union and others see the new regulation as license to discriminate.
“Once again, this administration shows itself to be determined to use religious liberty to harm communities it deems less worthy of equal treatment under the law,” Louise Melling, ACLU deputy legal director, said in a statement. “This rule threatens to prevent people from accessing critical medical care and may endanger people’s lives. Religious liberty is a fundamental right, but it does not include the right to discriminate or harm others. Denying patients health care is not religious liberty. Discriminating against patients based on their gender or gender expression is not religious liberty. Medical standards, not religious beliefs, should guide medical care.”
The regulation does not yet have a scheduled publication date in the Federal Register, nor has it been posted as a preview document on the publication’s website. It will become effective 60 days after publication.
Health care professionals may not be compelled to provide medical care, including abortion services or even referrals, if they object on religious or moral grounds under a federal regulation finalized May 2.
The regulation also requires health care entities that receive federal funding to alert their employees to their federal conscience rights.
This final rule “replaces a 2011 rule that has proven inadequate, and ensures that HHS implements the full set of tools appropriate for enforcing the conscience protections passed by Congress,” HHS officials said in a statement. “These federal laws protect providers, individuals, and other health care entities from having to provide, participate in, pay for, provide coverage of, or refer for, services such as abortion, sterilization, or assisted suicide. It also includes conscience protections with respect to advance directives.”
The regulation was first proposed in January 2018, shortly after the formation of the Conscience and Religious Freedom Division within the HHS Office of Civil Rights (OCR).
Application of the regulation extends beyond the clinic and hospital. The regulation notes that, on a case-by-case basis, those providing emergency services such as EMTs or even ambulance drivers could be protected should they choose to exercise their conscience and not provide services based on their religious beliefs.
“With this final rule, the Department seeks to educate protected entities and covered entities as to their legal rights and obligations; to encourage individuals and organizations with religious beliefs or moral convictions to enter, or remain in, the health care industry; and to prevent others from being dissuaded from filing complaints due to prior OCR complaint resolutions or sub-regulatory guidance that no reflect the views of the Department,” according to the regulation.
HHS officials denied accusations that the regulation puts the needs of providers over those of patients.
By “protecting a diversity of beliefs among health care providers, these protections ensure that options are available to patients who desire, and would feel most comfortable with, a provider whose religious beliefs or moral convictions match their own. Even where a patient and provider do not share the same religious beliefs or moral convictions, it is not necessarily the case that patients would want providers to be forced to violate their religious beliefs or moral convictions,” according to the regulation.
However, the American Civil Liberties Union and others see the new regulation as license to discriminate.
“Once again, this administration shows itself to be determined to use religious liberty to harm communities it deems less worthy of equal treatment under the law,” Louise Melling, ACLU deputy legal director, said in a statement. “This rule threatens to prevent people from accessing critical medical care and may endanger people’s lives. Religious liberty is a fundamental right, but it does not include the right to discriminate or harm others. Denying patients health care is not religious liberty. Discriminating against patients based on their gender or gender expression is not religious liberty. Medical standards, not religious beliefs, should guide medical care.”
The regulation does not yet have a scheduled publication date in the Federal Register, nor has it been posted as a preview document on the publication’s website. It will become effective 60 days after publication.
Isradipine for Parkinson’s disease fails in phase 3 study
PHILADELPHIA - There was no significant difference in Unified Parkinson’s Disease Rating Scale (UPDRS) scores between patients who received the calcium channel blocker isradipine and those who received placebo, according to the final results of the STEADY-PD III study, which will be presented at the annual meeting of the American Academy of Neurology.
Use of the drug to treat high blood pressure has been linked to lower risk of developing Parkinson’s disease, said study author Tanya Simuni, MD, a professor of neurology at Northwestern University, Chicago, in a news release.
“Unfortunately, the people who were taking isradipine did not have any difference in their Parkinson’s symptoms over the 3 years of the study, compared with the people who took a placebo,” Dr. Simuni said in the press release.
Hopes were high that isradipine might be the first drug to slow progression of Parkinson’s disease after promising animal studies and a phase 2 study showing no safety concerns, according to the news release.
The STEADY-PD III study, which was conducted at 54 Parkinson Study Group sites in the United States and Canada, included 336 participants with early Parkinson’s disease randomized to isradipine 10 mg daily or placebo. The median age of patients in the study was 62 years, and 68% were male. The median time from diagnosis was 0.9 years, and the mean UPDRS I-III score at baseline was 23.1, according to an abstract describing the study results.
The primary endpoint was change in UPDRS Part I-III score measured in the ON state from baseline to month 36 of treatment. That change over 36 months was 2.99 points in the isradipine arm and 3.26 points in the placebo arm, for a treatment effect of 0.27 points (95% confidence interval, –2.5 to 3.0; P = 0.85), investigators reported in the abstract. Adjustment for use of symptomatic therapy did not affect the comparison, the researchers noted.
Isradipine had no effect on secondary outcomes, including change in UPDRS-III in the OFF state, use of dopaminergic therapy, motor complications, or quality of life, investigators said in the abstract. Edema was the most notable side effect of isradipine treatment, investigators said.
These findings are “disappointing” but will not deter researchers in their work to find a treatment that will slow Parkinson’s disease progression, Dr. Simuni said in the news release. “Negative results are important because they provide a clear answer, especially for a drug that is commercially available,” she added.
Secondary analyses in progress will explore “biological and clinical correlates of disease progression” among the study participants, researchers said in their study abstract.
The study was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and also received some funding from The Michael J. Fox Foundation for Parkinson’s Research. Dr. Simuni reported disclosures related to AbbVie, Acadia, Accorda, Adamas, Allergan, Anavex, Biogen, Denali, the Michael J. Fox Foundation, Neurocrine, NeuroDerm, NINDS, the Parkinson Foundation, PhotoPharmics, Revance, Roche, Sanofi, Sunovion, Sun Pharma, Takeda, Teva, Voyager, and US World Meds.
PHILADELPHIA - There was no significant difference in Unified Parkinson’s Disease Rating Scale (UPDRS) scores between patients who received the calcium channel blocker isradipine and those who received placebo, according to the final results of the STEADY-PD III study, which will be presented at the annual meeting of the American Academy of Neurology.
Use of the drug to treat high blood pressure has been linked to lower risk of developing Parkinson’s disease, said study author Tanya Simuni, MD, a professor of neurology at Northwestern University, Chicago, in a news release.
“Unfortunately, the people who were taking isradipine did not have any difference in their Parkinson’s symptoms over the 3 years of the study, compared with the people who took a placebo,” Dr. Simuni said in the press release.
Hopes were high that isradipine might be the first drug to slow progression of Parkinson’s disease after promising animal studies and a phase 2 study showing no safety concerns, according to the news release.
The STEADY-PD III study, which was conducted at 54 Parkinson Study Group sites in the United States and Canada, included 336 participants with early Parkinson’s disease randomized to isradipine 10 mg daily or placebo. The median age of patients in the study was 62 years, and 68% were male. The median time from diagnosis was 0.9 years, and the mean UPDRS I-III score at baseline was 23.1, according to an abstract describing the study results.
The primary endpoint was change in UPDRS Part I-III score measured in the ON state from baseline to month 36 of treatment. That change over 36 months was 2.99 points in the isradipine arm and 3.26 points in the placebo arm, for a treatment effect of 0.27 points (95% confidence interval, –2.5 to 3.0; P = 0.85), investigators reported in the abstract. Adjustment for use of symptomatic therapy did not affect the comparison, the researchers noted.
Isradipine had no effect on secondary outcomes, including change in UPDRS-III in the OFF state, use of dopaminergic therapy, motor complications, or quality of life, investigators said in the abstract. Edema was the most notable side effect of isradipine treatment, investigators said.
These findings are “disappointing” but will not deter researchers in their work to find a treatment that will slow Parkinson’s disease progression, Dr. Simuni said in the news release. “Negative results are important because they provide a clear answer, especially for a drug that is commercially available,” she added.
Secondary analyses in progress will explore “biological and clinical correlates of disease progression” among the study participants, researchers said in their study abstract.
The study was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and also received some funding from The Michael J. Fox Foundation for Parkinson’s Research. Dr. Simuni reported disclosures related to AbbVie, Acadia, Accorda, Adamas, Allergan, Anavex, Biogen, Denali, the Michael J. Fox Foundation, Neurocrine, NeuroDerm, NINDS, the Parkinson Foundation, PhotoPharmics, Revance, Roche, Sanofi, Sunovion, Sun Pharma, Takeda, Teva, Voyager, and US World Meds.
PHILADELPHIA - There was no significant difference in Unified Parkinson’s Disease Rating Scale (UPDRS) scores between patients who received the calcium channel blocker isradipine and those who received placebo, according to the final results of the STEADY-PD III study, which will be presented at the annual meeting of the American Academy of Neurology.
Use of the drug to treat high blood pressure has been linked to lower risk of developing Parkinson’s disease, said study author Tanya Simuni, MD, a professor of neurology at Northwestern University, Chicago, in a news release.
“Unfortunately, the people who were taking isradipine did not have any difference in their Parkinson’s symptoms over the 3 years of the study, compared with the people who took a placebo,” Dr. Simuni said in the press release.
Hopes were high that isradipine might be the first drug to slow progression of Parkinson’s disease after promising animal studies and a phase 2 study showing no safety concerns, according to the news release.
The STEADY-PD III study, which was conducted at 54 Parkinson Study Group sites in the United States and Canada, included 336 participants with early Parkinson’s disease randomized to isradipine 10 mg daily or placebo. The median age of patients in the study was 62 years, and 68% were male. The median time from diagnosis was 0.9 years, and the mean UPDRS I-III score at baseline was 23.1, according to an abstract describing the study results.
The primary endpoint was change in UPDRS Part I-III score measured in the ON state from baseline to month 36 of treatment. That change over 36 months was 2.99 points in the isradipine arm and 3.26 points in the placebo arm, for a treatment effect of 0.27 points (95% confidence interval, –2.5 to 3.0; P = 0.85), investigators reported in the abstract. Adjustment for use of symptomatic therapy did not affect the comparison, the researchers noted.
Isradipine had no effect on secondary outcomes, including change in UPDRS-III in the OFF state, use of dopaminergic therapy, motor complications, or quality of life, investigators said in the abstract. Edema was the most notable side effect of isradipine treatment, investigators said.
These findings are “disappointing” but will not deter researchers in their work to find a treatment that will slow Parkinson’s disease progression, Dr. Simuni said in the news release. “Negative results are important because they provide a clear answer, especially for a drug that is commercially available,” she added.
Secondary analyses in progress will explore “biological and clinical correlates of disease progression” among the study participants, researchers said in their study abstract.
The study was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and also received some funding from The Michael J. Fox Foundation for Parkinson’s Research. Dr. Simuni reported disclosures related to AbbVie, Acadia, Accorda, Adamas, Allergan, Anavex, Biogen, Denali, the Michael J. Fox Foundation, Neurocrine, NeuroDerm, NINDS, the Parkinson Foundation, PhotoPharmics, Revance, Roche, Sanofi, Sunovion, Sun Pharma, Takeda, Teva, Voyager, and US World Meds.
FROM AAN 2019
A telemedicine compromise
It’s late on a Thursday afternoon. Even through the six walls that separate you from the waiting room you can feel the impatient throng of families as you struggle to see the tympanic membrane of a feverish and uncooperative 3-year-old. You already have scraped his auditory canal once with your curette. Your gut tells you that he must have an otitis but deeper in your soul there are other voices reminding you that to make the diagnosis you must visualize his ear drum. Your skill and the technology on hand has failed you.
It’s a Sunday morning, weekend hours, and you are seeing a 12-year-old with a sore throat and fever. Her physical exam suggests that she has strep pharyngitis but the team member in charge of restocking supplies has forgotten to reorder rapid strep kits and you used the last one yesterday afternoon.
Do you ignore your training and treat these sick children with antibiotics?
If you are someone who perceives the world in black and white, your response to these scenarios is simple because you NEVER prescribe antibiotics without seeing a tympanic membrane or confirming your suspicion with a rapid strep test. There are unrealistic solutions that could include requesting an immediate ear/nose/throat consult or sending the patient on an hour-long odyssey to the hospital lab. But for the rest of us who see in shades of gray, we may have to compromise our principles and temporarily become poor antibiotic stewards. The question is, how often do you compromise? Once a week, once a month, twice a year, or twice a day?
A study published in Pediatrics looks at the issue of antibiotic stewardship as it relates to telemedicine (“Antibiotic Prescribing During Pediatrics Direct-to-Consumer Telemedicine Visits,” Pediatrics. 2019 May. doi: 10.1542/peds.2018-2491).
The investigators found that children with acute respiratory infections were more likely to receive antibiotics and less likely to receive guideline concordant management at direct-to-consumer (DTC) telemedicine visits than when they were seen by their primary care physician or at an urgent care center.
In their discussion, the researchers note several possible explanations for the discrepancies they observed. DTC telemedicine visits are limited by the devices used by the families and physicians and generally lack availability of otoscopy and strep testing. The authors also wonder whether “there may be differential expectations for antibiotics among children and parents who use DTC telemedicine versus in person care.” Does this mean that families who utilize DTC telemedicine undervalue in-person care and/or are willing to compromise by accepting what they may suspect is substandard care for the convenience of DTC telemedicine?
Which brings me to my point. A physician who accepts the challenge of seeing pediatric patients with acute respiratory illnesses knowing that he or she will not be able to visualize tympanic membranes or perform strep testing also has accepted the fact that he or she will be compromising the principles of antibiotic stewardship he or she must have – or maybe should have – learned in medical school or residency.
We all occasionally compromise our principles when technology fails us or when the situations are extraordinary. But I am troubled that there some physicians who are willing to practice in an environment in which they are aware that they will be compromising their antibiotic stewardship on a daily or even hourly basis.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
It’s late on a Thursday afternoon. Even through the six walls that separate you from the waiting room you can feel the impatient throng of families as you struggle to see the tympanic membrane of a feverish and uncooperative 3-year-old. You already have scraped his auditory canal once with your curette. Your gut tells you that he must have an otitis but deeper in your soul there are other voices reminding you that to make the diagnosis you must visualize his ear drum. Your skill and the technology on hand has failed you.
It’s a Sunday morning, weekend hours, and you are seeing a 12-year-old with a sore throat and fever. Her physical exam suggests that she has strep pharyngitis but the team member in charge of restocking supplies has forgotten to reorder rapid strep kits and you used the last one yesterday afternoon.
Do you ignore your training and treat these sick children with antibiotics?
If you are someone who perceives the world in black and white, your response to these scenarios is simple because you NEVER prescribe antibiotics without seeing a tympanic membrane or confirming your suspicion with a rapid strep test. There are unrealistic solutions that could include requesting an immediate ear/nose/throat consult or sending the patient on an hour-long odyssey to the hospital lab. But for the rest of us who see in shades of gray, we may have to compromise our principles and temporarily become poor antibiotic stewards. The question is, how often do you compromise? Once a week, once a month, twice a year, or twice a day?
A study published in Pediatrics looks at the issue of antibiotic stewardship as it relates to telemedicine (“Antibiotic Prescribing During Pediatrics Direct-to-Consumer Telemedicine Visits,” Pediatrics. 2019 May. doi: 10.1542/peds.2018-2491).
The investigators found that children with acute respiratory infections were more likely to receive antibiotics and less likely to receive guideline concordant management at direct-to-consumer (DTC) telemedicine visits than when they were seen by their primary care physician or at an urgent care center.
In their discussion, the researchers note several possible explanations for the discrepancies they observed. DTC telemedicine visits are limited by the devices used by the families and physicians and generally lack availability of otoscopy and strep testing. The authors also wonder whether “there may be differential expectations for antibiotics among children and parents who use DTC telemedicine versus in person care.” Does this mean that families who utilize DTC telemedicine undervalue in-person care and/or are willing to compromise by accepting what they may suspect is substandard care for the convenience of DTC telemedicine?
Which brings me to my point. A physician who accepts the challenge of seeing pediatric patients with acute respiratory illnesses knowing that he or she will not be able to visualize tympanic membranes or perform strep testing also has accepted the fact that he or she will be compromising the principles of antibiotic stewardship he or she must have – or maybe should have – learned in medical school or residency.
We all occasionally compromise our principles when technology fails us or when the situations are extraordinary. But I am troubled that there some physicians who are willing to practice in an environment in which they are aware that they will be compromising their antibiotic stewardship on a daily or even hourly basis.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
It’s late on a Thursday afternoon. Even through the six walls that separate you from the waiting room you can feel the impatient throng of families as you struggle to see the tympanic membrane of a feverish and uncooperative 3-year-old. You already have scraped his auditory canal once with your curette. Your gut tells you that he must have an otitis but deeper in your soul there are other voices reminding you that to make the diagnosis you must visualize his ear drum. Your skill and the technology on hand has failed you.
It’s a Sunday morning, weekend hours, and you are seeing a 12-year-old with a sore throat and fever. Her physical exam suggests that she has strep pharyngitis but the team member in charge of restocking supplies has forgotten to reorder rapid strep kits and you used the last one yesterday afternoon.
Do you ignore your training and treat these sick children with antibiotics?
If you are someone who perceives the world in black and white, your response to these scenarios is simple because you NEVER prescribe antibiotics without seeing a tympanic membrane or confirming your suspicion with a rapid strep test. There are unrealistic solutions that could include requesting an immediate ear/nose/throat consult or sending the patient on an hour-long odyssey to the hospital lab. But for the rest of us who see in shades of gray, we may have to compromise our principles and temporarily become poor antibiotic stewards. The question is, how often do you compromise? Once a week, once a month, twice a year, or twice a day?
A study published in Pediatrics looks at the issue of antibiotic stewardship as it relates to telemedicine (“Antibiotic Prescribing During Pediatrics Direct-to-Consumer Telemedicine Visits,” Pediatrics. 2019 May. doi: 10.1542/peds.2018-2491).
The investigators found that children with acute respiratory infections were more likely to receive antibiotics and less likely to receive guideline concordant management at direct-to-consumer (DTC) telemedicine visits than when they were seen by their primary care physician or at an urgent care center.
In their discussion, the researchers note several possible explanations for the discrepancies they observed. DTC telemedicine visits are limited by the devices used by the families and physicians and generally lack availability of otoscopy and strep testing. The authors also wonder whether “there may be differential expectations for antibiotics among children and parents who use DTC telemedicine versus in person care.” Does this mean that families who utilize DTC telemedicine undervalue in-person care and/or are willing to compromise by accepting what they may suspect is substandard care for the convenience of DTC telemedicine?
Which brings me to my point. A physician who accepts the challenge of seeing pediatric patients with acute respiratory illnesses knowing that he or she will not be able to visualize tympanic membranes or perform strep testing also has accepted the fact that he or she will be compromising the principles of antibiotic stewardship he or she must have – or maybe should have – learned in medical school or residency.
We all occasionally compromise our principles when technology fails us or when the situations are extraordinary. But I am troubled that there some physicians who are willing to practice in an environment in which they are aware that they will be compromising their antibiotic stewardship on a daily or even hourly basis.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].
CMS pushing primary care with two new payment models
“We’re launching CMS Primary Cares, an initiative of two new payment models that will enroll a quarter or more of traditional Medicare beneficiaries and a quarter of providers in arrangements that pay for keeping patients healthy, rather than ordering procedures,” Alex Azar, secretary of Health and Human Services, said April 22 during a press conference.
“Today’s announcement creates innovation in primary care that has the potential to entirely transform our fee-for-service system – which is about 65% of the Medicare program – into one that drives value,” Seema Verma, administrator of the Centers for Medicare & Medicaid Services, said during the press conference.
The voluntary models are an array of “new payment options that are all designed to reward [physicians] for keeping people healthy, improving quality of life and delivering positive health outcomes,” Ms. Verma said. “These models are intended to allow clinicians to focus on patient care, not billing, and to do what they’ve been trained to do.”
One option, the Primary Care First model, is aimed at small and solo primary care practices.
The model will “provide participating practices with a predictable payment stream, including a partial cap and some fee-for-service spend,” Ms. Verma said, adding that payments will be adjusted for performance in reducing hospitalizations.
Under Primary Care First, practices will receive a flat payment per beneficiary, allowing clinicians to focus more on care than on revenue cycle management, according to CMS. Practices will be able to receive bonuses of up to 50% or penalties of up to 10%, based on performance, as an incentive to reduce costs and improve quality. Performance will be assessed and paid quarterly. Specifics on the per-beneficiary payment were not released.
Participation in Primary Care First is limited to primary care professionals certified in internal medicine, general medicine, geriatric medicine, family medicine, and hospice and palliative medicine. Practices must provide services to at least 125 Medicare beneficiaries and primary care services must account for at least 70% of billing revenue. Practices also must have experience in value-based payments.
There also will be an option for enhanced payment for caring for patients with chronic illnesses.
“When a patient stays healthy and out of the hospital, these practices will get paid a bonus,” Secretary Azar said. “But if the patient ends up sicker than expected, these practices will bear responsibility for the extra spending up to a certain share of their practices’ revenue.”
More information about participating in the Primary Care First model will be available later in the spring of 2019, with the model launching in 2020.
A second option, the Direct Contracting model is “more ambitious and aimed at larger practices,” Mr. Azar said – those that serve at least 5,000 Medicare beneficiaries.
“Just like in Primary Care First, when patients have a better experience and stay healthier, these practices will make more money,” he continued. “But if patients end up sicker, Direct Contracting Practices will bear the risk for the extra health spending, not just at their own practice, but throughout the system.”
Options under the Direct Contracting model are designed for organizations ready to take on full financial risk that have experience managing large populations with accountable care organizations or working with Medicare Advantage plans, Ms. Verma explained.
The Direct Contracting model will start with two options. The Professional population-based payment (PBP) model offers a lower risk-sharing arrangement (50% savings/losses), while the Global PBP offers a 100% savings/losses risk-sharing arrangement.
CMS also is requesting information on a third payment model, the Geographic PBP model, which would have a similar risk-sharing arrangement as the Global PBP, but participants would assume responsibility for the total cost of care for all Medicare fee-for-service beneficiaries in a defined region.
This model also will launch in 2020.
The new Medicare primary care options were commended by quarters not always supportive of the current government.
Andy Slavitt, CMS administrator under President Obama, voiced his support for the new models.
“There are several watershed moments in the history of the Medicare program, like the coverage of prescription drugs and the shift to paying for better care,” he tweeted April 22. This announcement is “another one as it eases the connection of Medicare beneficiaries to a primary care physician and gives doctors the freedom, rewards, and tools to keep people healthy.”
He continued: “With this great starting point, even as CMS listens to input, physicians and patient groups should be considering who this helps move ... to a healthier country with a more sustainable system.”
The American Medical Association also voiced its support.
“Providing adequate financial support for high-quality primary care must be an essential element of any strategy to improve the quality and affordability of our country’s health care system, Gerald E. Harmon, MD, immediate past chair of the AMA Board of Trustees, said in a statement. “Many primary care physicians have been struggling to deliver the care their patients need and to financially sustain their practices under current Medicare payments. The new primary care payment models announced today will provide practices with more resources and more flexibility to deliver the highest-quality care to their patients.”
The American College of Physicians also noted their support of the new models.
“ACP is optimistic that the new models will emphasize the important role primary care plays in value-based care delivery, that models are voluntary and have a range of risk options, and that practices should use population health management data to reap potential benefits,” Robert McLean, MD, ACP president, said in a statement.
The success and viability of these models will depend on the extent that they are supported by payers in addition to Medicare and Medicaid, are adequately adjusted for differences in the risk and health status of patients seen by each practice, are provided predictable and adequate payments to support and sustain practices (especially smaller independent ones), are appropriately scaled for the financial risk expected of a practice, are provided meaningful and timely data to support improvement, and are truly able to reduce administrative tasks and costs, among other things.”
We are pretty excited about Primary Care First, for what it symbolizes.
The academy has long suggested that fee for service is not congruent with the core elements of advanced primary care, and our internal policies have asked for payments for primary care patients to be realigned in a way that would facilitate or drive this type of care.
There are a lot of details that we need to understand, but I think this model represents a really significant step towards prospective population-based payments. This model enables primary care physicians to continue to provide continuous and comprehensive care to their patients. It is a big step away from fee for service and we think that’s good for primary care.
I think primary care when it functions at its best really relies upon three elements; continuity and comprehensiveness are probably the two most important elements, and the third is coordination. These three elements are associated with better outcomes and lower cost in several studies. The idea that a patient would have a longitudinal (continuous) relationship with a primary care physician who provides comprehensive services is a desired policy objective.
This model, by implementing prospective, per patient payments, allows practices to focus on longitudinal patient-centered care versus episodes of care that drive revenue. The fee for service, in contrast, offers a payment by service, so it creates individual episodes of care. For the last decade we have questioned whether fee for service can really drive the key elements of primary care of the patient.
There’s always a place for fee for service, but as a foundation, I think the prospective nature of payments is a really important element of what the CMS did. Since physicians would receive payments in advance for providing comprehensive care, they won’t have to generate services to manage their revenue cycle.
I think the Direct Contracting payment model is interesting in that it requires a practice to have a minimum of 5,000 beneficiaries and involves the practice taking on risk for a large population of people. There are a lot more questions on the direct contracting side, but I think, philosophically, we could see why it would be a successful payment model.
From a 30,000 foot perspective, the Primary Care First program should allow any physician practice, regardless of size, to participate. It’s conceivable even for a solo practice to participate in this model.
Our main concern about this model is its geographic restrictions, and we would like to see more states added to this program quickly.
R. Shawn Martin is president of advocacy, practice advancement and policy of the American Academy of Family Physicians. He made these comments in an interview.
We are pretty excited about Primary Care First, for what it symbolizes.
The academy has long suggested that fee for service is not congruent with the core elements of advanced primary care, and our internal policies have asked for payments for primary care patients to be realigned in a way that would facilitate or drive this type of care.
There are a lot of details that we need to understand, but I think this model represents a really significant step towards prospective population-based payments. This model enables primary care physicians to continue to provide continuous and comprehensive care to their patients. It is a big step away from fee for service and we think that’s good for primary care.
I think primary care when it functions at its best really relies upon three elements; continuity and comprehensiveness are probably the two most important elements, and the third is coordination. These three elements are associated with better outcomes and lower cost in several studies. The idea that a patient would have a longitudinal (continuous) relationship with a primary care physician who provides comprehensive services is a desired policy objective.
This model, by implementing prospective, per patient payments, allows practices to focus on longitudinal patient-centered care versus episodes of care that drive revenue. The fee for service, in contrast, offers a payment by service, so it creates individual episodes of care. For the last decade we have questioned whether fee for service can really drive the key elements of primary care of the patient.
There’s always a place for fee for service, but as a foundation, I think the prospective nature of payments is a really important element of what the CMS did. Since physicians would receive payments in advance for providing comprehensive care, they won’t have to generate services to manage their revenue cycle.
I think the Direct Contracting payment model is interesting in that it requires a practice to have a minimum of 5,000 beneficiaries and involves the practice taking on risk for a large population of people. There are a lot more questions on the direct contracting side, but I think, philosophically, we could see why it would be a successful payment model.
From a 30,000 foot perspective, the Primary Care First program should allow any physician practice, regardless of size, to participate. It’s conceivable even for a solo practice to participate in this model.
Our main concern about this model is its geographic restrictions, and we would like to see more states added to this program quickly.
R. Shawn Martin is president of advocacy, practice advancement and policy of the American Academy of Family Physicians. He made these comments in an interview.
We are pretty excited about Primary Care First, for what it symbolizes.
The academy has long suggested that fee for service is not congruent with the core elements of advanced primary care, and our internal policies have asked for payments for primary care patients to be realigned in a way that would facilitate or drive this type of care.
There are a lot of details that we need to understand, but I think this model represents a really significant step towards prospective population-based payments. This model enables primary care physicians to continue to provide continuous and comprehensive care to their patients. It is a big step away from fee for service and we think that’s good for primary care.
I think primary care when it functions at its best really relies upon three elements; continuity and comprehensiveness are probably the two most important elements, and the third is coordination. These three elements are associated with better outcomes and lower cost in several studies. The idea that a patient would have a longitudinal (continuous) relationship with a primary care physician who provides comprehensive services is a desired policy objective.
This model, by implementing prospective, per patient payments, allows practices to focus on longitudinal patient-centered care versus episodes of care that drive revenue. The fee for service, in contrast, offers a payment by service, so it creates individual episodes of care. For the last decade we have questioned whether fee for service can really drive the key elements of primary care of the patient.
There’s always a place for fee for service, but as a foundation, I think the prospective nature of payments is a really important element of what the CMS did. Since physicians would receive payments in advance for providing comprehensive care, they won’t have to generate services to manage their revenue cycle.
I think the Direct Contracting payment model is interesting in that it requires a practice to have a minimum of 5,000 beneficiaries and involves the practice taking on risk for a large population of people. There are a lot more questions on the direct contracting side, but I think, philosophically, we could see why it would be a successful payment model.
From a 30,000 foot perspective, the Primary Care First program should allow any physician practice, regardless of size, to participate. It’s conceivable even for a solo practice to participate in this model.
Our main concern about this model is its geographic restrictions, and we would like to see more states added to this program quickly.
R. Shawn Martin is president of advocacy, practice advancement and policy of the American Academy of Family Physicians. He made these comments in an interview.
“We’re launching CMS Primary Cares, an initiative of two new payment models that will enroll a quarter or more of traditional Medicare beneficiaries and a quarter of providers in arrangements that pay for keeping patients healthy, rather than ordering procedures,” Alex Azar, secretary of Health and Human Services, said April 22 during a press conference.
“Today’s announcement creates innovation in primary care that has the potential to entirely transform our fee-for-service system – which is about 65% of the Medicare program – into one that drives value,” Seema Verma, administrator of the Centers for Medicare & Medicaid Services, said during the press conference.
The voluntary models are an array of “new payment options that are all designed to reward [physicians] for keeping people healthy, improving quality of life and delivering positive health outcomes,” Ms. Verma said. “These models are intended to allow clinicians to focus on patient care, not billing, and to do what they’ve been trained to do.”
One option, the Primary Care First model, is aimed at small and solo primary care practices.
The model will “provide participating practices with a predictable payment stream, including a partial cap and some fee-for-service spend,” Ms. Verma said, adding that payments will be adjusted for performance in reducing hospitalizations.
Under Primary Care First, practices will receive a flat payment per beneficiary, allowing clinicians to focus more on care than on revenue cycle management, according to CMS. Practices will be able to receive bonuses of up to 50% or penalties of up to 10%, based on performance, as an incentive to reduce costs and improve quality. Performance will be assessed and paid quarterly. Specifics on the per-beneficiary payment were not released.
Participation in Primary Care First is limited to primary care professionals certified in internal medicine, general medicine, geriatric medicine, family medicine, and hospice and palliative medicine. Practices must provide services to at least 125 Medicare beneficiaries and primary care services must account for at least 70% of billing revenue. Practices also must have experience in value-based payments.
There also will be an option for enhanced payment for caring for patients with chronic illnesses.
“When a patient stays healthy and out of the hospital, these practices will get paid a bonus,” Secretary Azar said. “But if the patient ends up sicker than expected, these practices will bear responsibility for the extra spending up to a certain share of their practices’ revenue.”
More information about participating in the Primary Care First model will be available later in the spring of 2019, with the model launching in 2020.
A second option, the Direct Contracting model is “more ambitious and aimed at larger practices,” Mr. Azar said – those that serve at least 5,000 Medicare beneficiaries.
“Just like in Primary Care First, when patients have a better experience and stay healthier, these practices will make more money,” he continued. “But if patients end up sicker, Direct Contracting Practices will bear the risk for the extra health spending, not just at their own practice, but throughout the system.”
Options under the Direct Contracting model are designed for organizations ready to take on full financial risk that have experience managing large populations with accountable care organizations or working with Medicare Advantage plans, Ms. Verma explained.
The Direct Contracting model will start with two options. The Professional population-based payment (PBP) model offers a lower risk-sharing arrangement (50% savings/losses), while the Global PBP offers a 100% savings/losses risk-sharing arrangement.
CMS also is requesting information on a third payment model, the Geographic PBP model, which would have a similar risk-sharing arrangement as the Global PBP, but participants would assume responsibility for the total cost of care for all Medicare fee-for-service beneficiaries in a defined region.
This model also will launch in 2020.
The new Medicare primary care options were commended by quarters not always supportive of the current government.
Andy Slavitt, CMS administrator under President Obama, voiced his support for the new models.
“There are several watershed moments in the history of the Medicare program, like the coverage of prescription drugs and the shift to paying for better care,” he tweeted April 22. This announcement is “another one as it eases the connection of Medicare beneficiaries to a primary care physician and gives doctors the freedom, rewards, and tools to keep people healthy.”
He continued: “With this great starting point, even as CMS listens to input, physicians and patient groups should be considering who this helps move ... to a healthier country with a more sustainable system.”
The American Medical Association also voiced its support.
“Providing adequate financial support for high-quality primary care must be an essential element of any strategy to improve the quality and affordability of our country’s health care system, Gerald E. Harmon, MD, immediate past chair of the AMA Board of Trustees, said in a statement. “Many primary care physicians have been struggling to deliver the care their patients need and to financially sustain their practices under current Medicare payments. The new primary care payment models announced today will provide practices with more resources and more flexibility to deliver the highest-quality care to their patients.”
The American College of Physicians also noted their support of the new models.
“ACP is optimistic that the new models will emphasize the important role primary care plays in value-based care delivery, that models are voluntary and have a range of risk options, and that practices should use population health management data to reap potential benefits,” Robert McLean, MD, ACP president, said in a statement.
The success and viability of these models will depend on the extent that they are supported by payers in addition to Medicare and Medicaid, are adequately adjusted for differences in the risk and health status of patients seen by each practice, are provided predictable and adequate payments to support and sustain practices (especially smaller independent ones), are appropriately scaled for the financial risk expected of a practice, are provided meaningful and timely data to support improvement, and are truly able to reduce administrative tasks and costs, among other things.”
“We’re launching CMS Primary Cares, an initiative of two new payment models that will enroll a quarter or more of traditional Medicare beneficiaries and a quarter of providers in arrangements that pay for keeping patients healthy, rather than ordering procedures,” Alex Azar, secretary of Health and Human Services, said April 22 during a press conference.
“Today’s announcement creates innovation in primary care that has the potential to entirely transform our fee-for-service system – which is about 65% of the Medicare program – into one that drives value,” Seema Verma, administrator of the Centers for Medicare & Medicaid Services, said during the press conference.
The voluntary models are an array of “new payment options that are all designed to reward [physicians] for keeping people healthy, improving quality of life and delivering positive health outcomes,” Ms. Verma said. “These models are intended to allow clinicians to focus on patient care, not billing, and to do what they’ve been trained to do.”
One option, the Primary Care First model, is aimed at small and solo primary care practices.
The model will “provide participating practices with a predictable payment stream, including a partial cap and some fee-for-service spend,” Ms. Verma said, adding that payments will be adjusted for performance in reducing hospitalizations.
Under Primary Care First, practices will receive a flat payment per beneficiary, allowing clinicians to focus more on care than on revenue cycle management, according to CMS. Practices will be able to receive bonuses of up to 50% or penalties of up to 10%, based on performance, as an incentive to reduce costs and improve quality. Performance will be assessed and paid quarterly. Specifics on the per-beneficiary payment were not released.
Participation in Primary Care First is limited to primary care professionals certified in internal medicine, general medicine, geriatric medicine, family medicine, and hospice and palliative medicine. Practices must provide services to at least 125 Medicare beneficiaries and primary care services must account for at least 70% of billing revenue. Practices also must have experience in value-based payments.
There also will be an option for enhanced payment for caring for patients with chronic illnesses.
“When a patient stays healthy and out of the hospital, these practices will get paid a bonus,” Secretary Azar said. “But if the patient ends up sicker than expected, these practices will bear responsibility for the extra spending up to a certain share of their practices’ revenue.”
More information about participating in the Primary Care First model will be available later in the spring of 2019, with the model launching in 2020.
A second option, the Direct Contracting model is “more ambitious and aimed at larger practices,” Mr. Azar said – those that serve at least 5,000 Medicare beneficiaries.
“Just like in Primary Care First, when patients have a better experience and stay healthier, these practices will make more money,” he continued. “But if patients end up sicker, Direct Contracting Practices will bear the risk for the extra health spending, not just at their own practice, but throughout the system.”
Options under the Direct Contracting model are designed for organizations ready to take on full financial risk that have experience managing large populations with accountable care organizations or working with Medicare Advantage plans, Ms. Verma explained.
The Direct Contracting model will start with two options. The Professional population-based payment (PBP) model offers a lower risk-sharing arrangement (50% savings/losses), while the Global PBP offers a 100% savings/losses risk-sharing arrangement.
CMS also is requesting information on a third payment model, the Geographic PBP model, which would have a similar risk-sharing arrangement as the Global PBP, but participants would assume responsibility for the total cost of care for all Medicare fee-for-service beneficiaries in a defined region.
This model also will launch in 2020.
The new Medicare primary care options were commended by quarters not always supportive of the current government.
Andy Slavitt, CMS administrator under President Obama, voiced his support for the new models.
“There are several watershed moments in the history of the Medicare program, like the coverage of prescription drugs and the shift to paying for better care,” he tweeted April 22. This announcement is “another one as it eases the connection of Medicare beneficiaries to a primary care physician and gives doctors the freedom, rewards, and tools to keep people healthy.”
He continued: “With this great starting point, even as CMS listens to input, physicians and patient groups should be considering who this helps move ... to a healthier country with a more sustainable system.”
The American Medical Association also voiced its support.
“Providing adequate financial support for high-quality primary care must be an essential element of any strategy to improve the quality and affordability of our country’s health care system, Gerald E. Harmon, MD, immediate past chair of the AMA Board of Trustees, said in a statement. “Many primary care physicians have been struggling to deliver the care their patients need and to financially sustain their practices under current Medicare payments. The new primary care payment models announced today will provide practices with more resources and more flexibility to deliver the highest-quality care to their patients.”
The American College of Physicians also noted their support of the new models.
“ACP is optimistic that the new models will emphasize the important role primary care plays in value-based care delivery, that models are voluntary and have a range of risk options, and that practices should use population health management data to reap potential benefits,” Robert McLean, MD, ACP president, said in a statement.
The success and viability of these models will depend on the extent that they are supported by payers in addition to Medicare and Medicaid, are adequately adjusted for differences in the risk and health status of patients seen by each practice, are provided predictable and adequate payments to support and sustain practices (especially smaller independent ones), are appropriately scaled for the financial risk expected of a practice, are provided meaningful and timely data to support improvement, and are truly able to reduce administrative tasks and costs, among other things.”
Myc signaling, monocytes predict NSCLC response to second-line entinostat + pembro
ATLANTA – Combination entinostat and pembrolizumab showed promising activity in a phase 2 study of non–small cell lung cancer patients who progressed on or after anti-programmed death-ligand 1 (PD-L1) therapy, and new analyses have identified gene signatures associated with treatment response.
Gene set analysis in tumors from 43 of the patients – 4 responders and 39 nonresponders – who participated in the open-label ENCORE-601 study revealed that Myc gene signaling was enriched in responders vs. nonresponders, Suresh S. Ramalingam, MD, said at the annual meeting of the American Association for Cancer Research.
High Myc gene activity is known from previous studies to be associated with response to immune checkpoint inhibition, and this has been attributed to high PD-L1 expression, decrease in interferon signatures, and exclusion of lymphocytes, he noted.
“And we know from other publications that entinostat is known to decrease Myc activity,” he said. “Therefore, our putative hypothesis at this time – albeit on a small set of patients – is that for patients with baseline high Myc activity, when they have developed resistance to PD-1 or PD-L1 inhibition ... giving them entinostat drives down the Myc activity and results in a change in the tumor microenvironment to one where immune checkpoint inhibition could be rendered effective.”
Patients from ENCORE-601 also were evaluated by baseline circulating classical monocyte levels as prior findings showed improved overall survival and progression-free survival (PFS) in melanoma patients with higher vs. lower counts, Dr. Ramalingam explained.
The overall response rate (ORR) in those with baseline levels above the median (MHi, 11 patients) was 21.1% vs. 6.5% in those with levels below the median (MLo, 32 patients); median PFS was 4.7 vs. 2.7 months in the MHi and MLo groups, respectively, said Dr. Ramalingam of Winship Cancer Institute, Emory University, Atlanta.
ENCORE-601 included 76 subjects who received entinostat at a dose of 5 mg per week plus intravenous pembrolizumab at 200 mg every 3 weeks. The confirmed ORR with treatment in 72 efficacy-evaluable patients was 10%, with an additional 50% of patients having stable disease. The median duration of response was 8 months, and median PFS was 2.8 months.
Top-line results from the study, which was undertaken based in part on preclinical data showing synergy between the oral class 1-selective histone deacetylase inhibitor entinostat and anti-PD-1 inhibition, were presented at the 2018 World Conference on Lung Cancer, and the current findings represent secondary outcome measures involving analyses in pretreatment tumor samples from patients with sufficient RNA yield for analysis.
The data may provide a mechanistic basis for the responses seen with entinostat and pembrolizumab in ENCORE-601, Dr. Ramalingam said.
“Now we acknowledge that this is a relatively small dataset, and therefore further studies are warranted using these biomarkers to further understand whether they can be used as predictive biomarkers for treatment,” he said, noting that one such clinical trial is currently in the discussion phase.
The ENCORE-601 findings are important given that “with the movement of checkpoint inhibitors to the front-line setting, there is now an unmet need in the second-line [setting] where patients have already received a checkpoint inhibitor and have developed disease progression,” he noted, adding that “while chemotherapy remains central to this group of patients, development of novel agents is an unmet need.”
Dr. Ramalingam disclosed ties to AbbVie, Advaxis, Amgen, Astra Zeneca, Bristol-Myers Squibb, Genentech/Roche, Loxo, Merck, Nektar, Takeda, and Syndax.
SOURCE: Ramalingam S et al. AACR 2019, Abstract CT041.
ATLANTA – Combination entinostat and pembrolizumab showed promising activity in a phase 2 study of non–small cell lung cancer patients who progressed on or after anti-programmed death-ligand 1 (PD-L1) therapy, and new analyses have identified gene signatures associated with treatment response.
Gene set analysis in tumors from 43 of the patients – 4 responders and 39 nonresponders – who participated in the open-label ENCORE-601 study revealed that Myc gene signaling was enriched in responders vs. nonresponders, Suresh S. Ramalingam, MD, said at the annual meeting of the American Association for Cancer Research.
High Myc gene activity is known from previous studies to be associated with response to immune checkpoint inhibition, and this has been attributed to high PD-L1 expression, decrease in interferon signatures, and exclusion of lymphocytes, he noted.
“And we know from other publications that entinostat is known to decrease Myc activity,” he said. “Therefore, our putative hypothesis at this time – albeit on a small set of patients – is that for patients with baseline high Myc activity, when they have developed resistance to PD-1 or PD-L1 inhibition ... giving them entinostat drives down the Myc activity and results in a change in the tumor microenvironment to one where immune checkpoint inhibition could be rendered effective.”
Patients from ENCORE-601 also were evaluated by baseline circulating classical monocyte levels as prior findings showed improved overall survival and progression-free survival (PFS) in melanoma patients with higher vs. lower counts, Dr. Ramalingam explained.
The overall response rate (ORR) in those with baseline levels above the median (MHi, 11 patients) was 21.1% vs. 6.5% in those with levels below the median (MLo, 32 patients); median PFS was 4.7 vs. 2.7 months in the MHi and MLo groups, respectively, said Dr. Ramalingam of Winship Cancer Institute, Emory University, Atlanta.
ENCORE-601 included 76 subjects who received entinostat at a dose of 5 mg per week plus intravenous pembrolizumab at 200 mg every 3 weeks. The confirmed ORR with treatment in 72 efficacy-evaluable patients was 10%, with an additional 50% of patients having stable disease. The median duration of response was 8 months, and median PFS was 2.8 months.
Top-line results from the study, which was undertaken based in part on preclinical data showing synergy between the oral class 1-selective histone deacetylase inhibitor entinostat and anti-PD-1 inhibition, were presented at the 2018 World Conference on Lung Cancer, and the current findings represent secondary outcome measures involving analyses in pretreatment tumor samples from patients with sufficient RNA yield for analysis.
The data may provide a mechanistic basis for the responses seen with entinostat and pembrolizumab in ENCORE-601, Dr. Ramalingam said.
“Now we acknowledge that this is a relatively small dataset, and therefore further studies are warranted using these biomarkers to further understand whether they can be used as predictive biomarkers for treatment,” he said, noting that one such clinical trial is currently in the discussion phase.
The ENCORE-601 findings are important given that “with the movement of checkpoint inhibitors to the front-line setting, there is now an unmet need in the second-line [setting] where patients have already received a checkpoint inhibitor and have developed disease progression,” he noted, adding that “while chemotherapy remains central to this group of patients, development of novel agents is an unmet need.”
Dr. Ramalingam disclosed ties to AbbVie, Advaxis, Amgen, Astra Zeneca, Bristol-Myers Squibb, Genentech/Roche, Loxo, Merck, Nektar, Takeda, and Syndax.
SOURCE: Ramalingam S et al. AACR 2019, Abstract CT041.
ATLANTA – Combination entinostat and pembrolizumab showed promising activity in a phase 2 study of non–small cell lung cancer patients who progressed on or after anti-programmed death-ligand 1 (PD-L1) therapy, and new analyses have identified gene signatures associated with treatment response.
Gene set analysis in tumors from 43 of the patients – 4 responders and 39 nonresponders – who participated in the open-label ENCORE-601 study revealed that Myc gene signaling was enriched in responders vs. nonresponders, Suresh S. Ramalingam, MD, said at the annual meeting of the American Association for Cancer Research.
High Myc gene activity is known from previous studies to be associated with response to immune checkpoint inhibition, and this has been attributed to high PD-L1 expression, decrease in interferon signatures, and exclusion of lymphocytes, he noted.
“And we know from other publications that entinostat is known to decrease Myc activity,” he said. “Therefore, our putative hypothesis at this time – albeit on a small set of patients – is that for patients with baseline high Myc activity, when they have developed resistance to PD-1 or PD-L1 inhibition ... giving them entinostat drives down the Myc activity and results in a change in the tumor microenvironment to one where immune checkpoint inhibition could be rendered effective.”
Patients from ENCORE-601 also were evaluated by baseline circulating classical monocyte levels as prior findings showed improved overall survival and progression-free survival (PFS) in melanoma patients with higher vs. lower counts, Dr. Ramalingam explained.
The overall response rate (ORR) in those with baseline levels above the median (MHi, 11 patients) was 21.1% vs. 6.5% in those with levels below the median (MLo, 32 patients); median PFS was 4.7 vs. 2.7 months in the MHi and MLo groups, respectively, said Dr. Ramalingam of Winship Cancer Institute, Emory University, Atlanta.
ENCORE-601 included 76 subjects who received entinostat at a dose of 5 mg per week plus intravenous pembrolizumab at 200 mg every 3 weeks. The confirmed ORR with treatment in 72 efficacy-evaluable patients was 10%, with an additional 50% of patients having stable disease. The median duration of response was 8 months, and median PFS was 2.8 months.
Top-line results from the study, which was undertaken based in part on preclinical data showing synergy between the oral class 1-selective histone deacetylase inhibitor entinostat and anti-PD-1 inhibition, were presented at the 2018 World Conference on Lung Cancer, and the current findings represent secondary outcome measures involving analyses in pretreatment tumor samples from patients with sufficient RNA yield for analysis.
The data may provide a mechanistic basis for the responses seen with entinostat and pembrolizumab in ENCORE-601, Dr. Ramalingam said.
“Now we acknowledge that this is a relatively small dataset, and therefore further studies are warranted using these biomarkers to further understand whether they can be used as predictive biomarkers for treatment,” he said, noting that one such clinical trial is currently in the discussion phase.
The ENCORE-601 findings are important given that “with the movement of checkpoint inhibitors to the front-line setting, there is now an unmet need in the second-line [setting] where patients have already received a checkpoint inhibitor and have developed disease progression,” he noted, adding that “while chemotherapy remains central to this group of patients, development of novel agents is an unmet need.”
Dr. Ramalingam disclosed ties to AbbVie, Advaxis, Amgen, Astra Zeneca, Bristol-Myers Squibb, Genentech/Roche, Loxo, Merck, Nektar, Takeda, and Syndax.
SOURCE: Ramalingam S et al. AACR 2019, Abstract CT041.
REPORTING FROM AACR 2019
2019 Update on cervical disease
Cervical cancer rates remain low in the United States, with the incidence having plateaued for decades. And yet, in 2019, more than 13,000 US women will be diagnosed with cervical cancer.1 Globally, in 2018 almost 600,000 women were diagnosed with cervical cancer2; it is the fourth most frequent cancer in women. This is despite the fact that we have adequate primary and secondary prevention tools available to minimize—and almost eliminate—cervical cancer. We must continue to raise the bar for preventing, screening for, and managing this disease.
Human papillomavirus (HPV) vaccines provide a highly effective primary prevention strategy, but we need to improve our ability to identify and diagnose dysplastic lesions prior to the development of cervical cancer. Highly sensitive HPV testing and cytology is a powerful secondary prevention approach that enables us to assess a woman’s risk of having precancerous cells both now and in the near future. These modalities have been very successful in decreasing the incidence of cervical cancer in the United States and other areas with organized screening programs. In low- and middle-income countries, however, access to, availability of, and performance with these modalities is not optimal. Innovative strategies and new technologies are being evaluated to overcome these limitations.
Advances in radiation and surgical technology have enabled us to vastly improve cervical cancer treatment. Women with early-stage cervical cancer are candidates for surgical management, which frequently includes a radical hysterectomy and lymph node dissection. While these surgeries traditionally have been performed via an exploratory laparotomy, minimally invasive techniques (laparoscopic and robot-assisted surgical techniques) have decreased the morbidity with these surgeries. Notable new studies have shed light on the comparative effectiveness of minimally invasive technologies and have shown us that new is not always better.
The US Preventive Services Task Force (USPSTF) recently released its updated cervical cancer screening guidelines. The suggested approach to screening differs from previous recommendations. HPV testing as a primary test (that is, HPV testing alone or followed by cytology) takes the spotlight now, according to the analysis by the Task Force.
In this Update, we highlight important studies published in the past year that address these issues.
Continue to: New tech's potential to identify high-grade...
New tech's potential to identify high-grade cervical dysplasia may be a boon to low-resource settings
Hu L, Bell D, Antani S, et al. An observational study of deep learning and automated evaluation of cervical images for cancer screening. J Natl Cancer Inst. 2019;doi:10.1093/jnci/djy225.
When cervical screening tests like cytology and HPV testing show abnormal results, colposcopy often is recommended. The goal of colposcopy is to identify the areas that might harbor a high-grade precancerous lesion or worse. The gold standard in this case, however, is histology, not colposcopic impression, as many studies have shown that colposcopy without biopsies is limited and that performance is improved with more biopsies.3,4
Visual inspection with acetic acid (VIA) is an approach used often in low-resource settings where visual impression is the gold standard. However, as with colposcopy, a visual evaluation without histology does not perform well, and often women are overtreated. Many attempts have been made with new technologies to overcome the limitations of time, cost, and workforce required for cytology and histology services. New disruptive technologies may be able to surmount human limitations and improve on not only VIA but also the need for histology.
Novel technology uses images to develop algorithm with predictive ability
In a recent observational study, Hu and colleagues used images that were collected during a large population study in Guanacaste, Costa Rica.5 More than 9,000 women were followed for up to 7 years, and cervical photographs (cervigrams) were obtained. Well-annotated histopathology results were obtained for women with abnormal screening, and 279 women had a high-grade dysplastic lesion or cancer.
Cervigrams from women with high-grade lesions and matched controls were collected, and a deep learning-based algorithm using artificial intelligence technology was developed using 70% of the images. The remaining 30% of images were used as a validation set to test the algorithm's ability to "predict" high-grade dysplasia without knowing the final result.
Findings. Termed automated visual evaluation (AVE), this new technology demonstrated a very accurate ability to identify high-grade dysplasia or worse, with an area under the curve (AUC) of 0.91 from merely a cervicogram (FIGURE). This outperformed conventional Pap smears (AUC, 0.71), liquid-based cytology (AUC, 0.79) and, surprisingly, highly sensitive HPV testing (AUC, 0.82) in women in the prime of their screening ages (>25 years of age).
Colposcopy remains the gold standard for evaluating abnormal cervical cancer screening tests in the United States. But can we do better for our patients using new technologies like AVE? If validated in large-scale trials, AVE has the potential to revolutionize cervical cancer screening in low-resource settings where follow-up and adequate histology services are limited or nonexistent. Future large studies are necessary to evaluate the role of AVE alone versus in combination with other diagnostic testing (such as HPV testing) to detect cervical lesions globally.
Continue to: Data offer persuasive evidence...
Data offer persuasive evidence to abandon minimally invasive surgery in management of early-stage cervical cancer
Melamed A, Margul DJ, Chen L, et al. Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med. 2018;379:1905-1914.
Ramirez PT, Frumovitz M, Pareja R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med. 2018;379:1895-1904.
Over the past decade, gynecologic cancer surgery has shifted from what routinely were open procedures to the adoption of minimally invasive techniques. Recently, a large, well-designed prospective study and a large retrospective study both demonstrated worse outcomes with minimally invasive radical hysterectomy (MIRH) as compared with traditional open radical abdominal hysterectomy (RAH). These 2 landmark studies, initially presented at the Society of Gynecologic Oncology's 2018 annual meeting and later published in the New England Journal of Medicine, have really affected the gynecologic oncology community.
Shorter overall survival in women who had MIRH
Melamed and colleagues conducted a large, retrospective US-based study to evaluate all-cause mortality in women with cervical cancer who underwent MIRH compared with those who had RAH.6 The authors also sought to evaluate national trends in 4-year relative survival rates after minimally invasive surgery was adopted.
The study included 2,461 women who met the inclusion criteria; 49.8% (1,225) underwent MIRH procedures and, of those, 79.8% (978) had robot-assisted laparoscopy. Most women had stage IB1 tumors (88%), and most carcinomas were squamous cell (61%); 40.6% of tumors were less than 2 cm in size. There were no differences between the 2 groups with respect to rates of positive parametria, surgical margins, and lymph node involvement. Administration of adjuvant therapy, in those who qualified, was also similar between groups.
Results. At a median follow-up of 45 months, 94 deaths occurred in the minimally invasive group and 70 in the open surgery group. The risk of death at 4 years was 9.1% in the minimally invasive group versus 5.3% in the open surgery group, with a 65% higher risk of death from any cause, which was highly statistically significant.
Prospective trial showed MIRH was associated with lower survival rates
From 2008 to 2017, Ramirez and colleagues conducted a phase 3, multicenter, randomized controlled trial to prospectively establish the noninferiority of MIRH compared with RAH.7 The study included 631 women from 33 centers. The prespecified expected disease-free survival rate was 90% at 4.5 years.
To be included as a site, centers were required to submit details from 10 minimally invasive cases as well as 2 unedited videos for review by the trial management committee. In contrast to Melamed and colleagues' retrospective study, of the 319 procedures that were classified as minimally invasive, only 15.6% were robotically assisted. Similarly, most women had stage IB1 tumors (91.9%), and most were squamous cell carcinomas (67%). There were also no differences in the postoperative pathology findings or the need for adjuvant therapy administered between groups. The median follow-up was 2.5 years.
Results. At that time there were 27 recurrences in the MIRH group and 7 in the RAH group; there were also 19 deaths after MIRH and 3 after RAH. Disease-free survival at 4.5 years was 86% with MIRH versus 96.5% with RAH. Reported 3-year disease-free survival and overall survival were also significantily lower in the minimally invasive subgroup (91.2% vs 97.1%, 93.8% vs 99.0%, respectively).
Study limitations. Criticisms of this trial are that noninferiority could not be declared; in addition, the investigators were unable to complete enrollment secondary to early enrollment termination after the data and safety monitoring board raised survival concerns.
Many argue that subgroup analyses suggest a lower risk of poor outcomes in patients with smaller tumors (<2 cm); however, it is critical to note that this study was not powered to detect these differences.
The evidence is compelling and demonstrates potentially worse disease-related outcomes using MIRH when compared to traditional RAH with respect to cervical cancer recurrence, rates of death, and disease-free and overall survival. Several hypotheses have been proposed, and future research is needed to elucidate the differences in variables responsible for the outcomes demonstrated in these studies. Although there has been no ban on robot-assisted surgical devices or traditional minimally invasive techniques, the National Comprehensive Cancer Network has updated its recommendations to include careful counseling of patients who require a surgical approach for the management of early-stage cervical cancer.
Continue to: USPSTF updated guidance on cervical cancer screening...
USPSTF updated guidance on cervical cancer screening
Melnikow J, Henderson JT, Burda BU, et al. Screening for cervical cancer with high-risk human papillomavirus testing: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2018;320:687-705.
US Preventive Services Task Force, Curry SJ, Krist AH, et al. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;320:674-686.
Past guidelines for cervical cancer screening have included testing for high-risk HPV (hrHPV) as a cotest with cytology or for triage of atypical squamous cells of undetermined significance (ASCUS) in women aged 30 to 65 years.8 The American Society for Colposcopy and Cervical Pathology and the Society of Gynecologic Oncology, with other stakeholder organizations, issued interim guidance for primary HPV testing--that is, HPV test first and, in the case of non-16/18 hrHPV types, cytology as a triage. The most recent evidence report and systematic review by Melnikow and colleagues for the USPSTF offers an in-depth analysis of risks, benefits, harms, and value of cotesting and other management strategies.9
Focus on screening effectiveness
Large trials of cotesting were conducted in women aged 25 to 65.10-13 These studies all consistently showed that primary hrHPV screening led to a statistically significant increased detection of cervical intraepithelial neoplasia (CIN) 3+ in the initial round of screening, with a relative risk of detecting CIN 3+ ranging from 1.61 to 7.46 compared with cytology alone.
Four additional studies compared cotesting with conventional cytology for the detection of CIN 3+. None of these trials demonstrated a significantly higher detection rate of CIN 3+ with cotesting compared with conventional cytology testing alone. Notably, the studies reviewed were performed in European countries that had organized screening programs in place and a nationalized health care system. Thus, these data may not be as applicable to women in the United States, particularly to women who have limited health care access.
Risks of screening
In the same studies reviewed for screening effectiveness, the investigators found that overall, screening with hrHPV primary or cotesting was associated with more false-positive results and higher colposcopy rates. Women screened with hrHPV alone had a 7.9% referral rate to colposcopy, while those screened with cytology had a 2.8% referral rate to colposcopy. Similarly, the rate of biopsy was higher in the hrHPV-only group (3.2% vs 1.3%).
Overall, while cotesting might have some improvement in performance compared with hrHPV as a single modality, there might be risks of overreferral to colposcopy and overtreatment with additional cytology over hrHPV testing alone.
This evidence review also included an analysis of more potential harms. Very limited evidence suggests that positive hrHPV test results may be associated with greater psychological harm, including decreased sexual satisfaction, increased anxiety and distress, and worse feelings about sexual partners, than abnormal cytology results. These were assessed, however, 1 to 2 weeks after the test results were provided to the patients, and long-term assessment was not done.
New recommendations from the USPSTF
Based on these data, the USPSTF issued new recommendations regarding screening (TABLE).14 For women aged 21 to 29, cytology alone should be used for screening every 3 years. Women aged 30 to 65 can be screened with cytology alone every 3 years, with hrHPV testing alone every 5 years, or with cotesting every 5 years.
Primary screening with hrHPV is more effective in diagnosing a CIN 3+ than cytology alone. Cotesting with cytology and hrHPV testing appears to have limited performance improvement, with potential harm, compared with hrHPV testing alone in diagnosing CIN 3+. The Task Force recommendation is hrHPV testing alone or cotesting every 5 years.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7-34.
- World Health Organization website. Cervical cancer. https://www.who.int/cancer/prevention/diagnosis-screening/cervical-cancer/en/. Accessed April 17, 2019.
- Wentzensen N, Walker JL, Gold MA, et al. Multiple biopsies and detection of cervical cancer precursors at colposcopy. J Clin Oncol. 2015;33:83-89.
- Gage JC, Hanson VW, Abbey K, et al. Number of cervical biopsies and sensitivity of colposcopy. Obstet Gynecol. 2006;108:264-272.
- Hu L, Bell D, Antani S, et al. An observational study of deep learning and automated evaluation of cervical images for cancer screening. J Natl Cancer Inst. 2019;doi:10.1093/jnci/djy225.
- Melamed A, Margul DJ, Chen L, et al. Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med. 2018;379:1905-1914.
- Ramirez PT, Frumovitz M, Pareja R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med. 2018;379:1895-1904.
- Saslow D, Solomon D, Lawson HW, et al; ACS-ASCCP-ASCP Cervical Cancer Guideline Committee. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012;62:147-172.
- Melnikow J, Henderson JT, Burda BU, et al. Screening for cervical cancer with high-risk human papillomavirus testing: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2018;320:687-705.
- Canfell K, Caruana M, Gebski V, et al. Cervical screening with primary HPV testing or cytology in a population of women in which those aged 33 years or younger had previously been offered HPV vaccination: results of the Compass pilot randomised trial. PLoS Med. 2017;14:e1002388. doi:10.1371/journal.pmed.1002388.
- Leinonen MK, Nieminen P, Lonnberg S, et al. Detection rates of precancerous and cancerous cervical lesions within one screening round of primary human papillomavirus DNA testing: prospective randomised trial in Finland. BMJ. 2012;345:e7789.
- Ogilvie GS, van Niekerk D, Krajden M, et al. Effect of screening with primary cervical HPV testing vs cytology testing on high-grade cervical intraepithelial neoplasia at 48 months: the HPV FOCAL randomized clinical trial. JAMA. 2018;320:43-52.
- Ronco G, Fioprgi-Rossi P, Carozzi F, et al; New Technologies for Cervical Cancer screening (NTCC) Working Group. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol. 2010;11:249-257.
- US Preventive Services Task Force, Curry SJ, Krist AH, et al. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;320:674-686.
Jenna Z. Marcus, MD
Dr. Marcus is Assistant Professor, Department of Obstetrics, Gynecology and Women’s Health, Rutgers New Jersey Medical School, Newark, New Jersey.
Akiva P. Novetsky, MD, MS
Dr. Novetsky is Associate Professor, Department of Obstetrics, Gynecology and Women’s Health, Rutgers New Jersey Medical School, Newark, New Jersey, and Chief Quality Officer, Rutgers Cancer Institute of New Jersey, New Brunswick.
Mark H. Einstein, MD, MS
Dr. Einstein is Professor and Chair, Department of Obstetrics, Gynecology and Women’s Health, and Assistant Dean, Clinical Research Unit, Rutgers New Jersey Medical School, Newark, New Jersey.
Dr. Einstein has advised or participated in educational speaking activities, but he does not receive an honorarium from any companies. In specific cases, Rutgers has received payment for his time spent for these activities from Photocure, Papivax, Cynvec, Merck, Hologic, and PDS Biotechnology. If travel is required for meetings with industry, the company pays for Dr. Einstein’s travel expenses. Rutgers has received grant funding for research-related costs of clinical trials that Dr. Einstein has been the overall or local principal investigator within the past 12 months from J&J, Pfizer, and Inovio. Rutgers has received payment for Dr. Einstein’s time from Photocure, Papivax, Cynvec, and PDS Biotechnology.
Dr. Novetsky is the overall principal investigator of an investigator-initiated grant sponsored by Roche. His institution, Rutgers, has received funding for the clinical costs of this trial.
Dr. Marcus reports no financial relationships relevant to this article.
Jenna Z. Marcus, MD
Dr. Marcus is Assistant Professor, Department of Obstetrics, Gynecology and Women’s Health, Rutgers New Jersey Medical School, Newark, New Jersey.
Akiva P. Novetsky, MD, MS
Dr. Novetsky is Associate Professor, Department of Obstetrics, Gynecology and Women’s Health, Rutgers New Jersey Medical School, Newark, New Jersey, and Chief Quality Officer, Rutgers Cancer Institute of New Jersey, New Brunswick.
Mark H. Einstein, MD, MS
Dr. Einstein is Professor and Chair, Department of Obstetrics, Gynecology and Women’s Health, and Assistant Dean, Clinical Research Unit, Rutgers New Jersey Medical School, Newark, New Jersey.
Dr. Einstein has advised or participated in educational speaking activities, but he does not receive an honorarium from any companies. In specific cases, Rutgers has received payment for his time spent for these activities from Photocure, Papivax, Cynvec, Merck, Hologic, and PDS Biotechnology. If travel is required for meetings with industry, the company pays for Dr. Einstein’s travel expenses. Rutgers has received grant funding for research-related costs of clinical trials that Dr. Einstein has been the overall or local principal investigator within the past 12 months from J&J, Pfizer, and Inovio. Rutgers has received payment for Dr. Einstein’s time from Photocure, Papivax, Cynvec, and PDS Biotechnology.
Dr. Novetsky is the overall principal investigator of an investigator-initiated grant sponsored by Roche. His institution, Rutgers, has received funding for the clinical costs of this trial.
Dr. Marcus reports no financial relationships relevant to this article.
Jenna Z. Marcus, MD
Dr. Marcus is Assistant Professor, Department of Obstetrics, Gynecology and Women’s Health, Rutgers New Jersey Medical School, Newark, New Jersey.
Akiva P. Novetsky, MD, MS
Dr. Novetsky is Associate Professor, Department of Obstetrics, Gynecology and Women’s Health, Rutgers New Jersey Medical School, Newark, New Jersey, and Chief Quality Officer, Rutgers Cancer Institute of New Jersey, New Brunswick.
Mark H. Einstein, MD, MS
Dr. Einstein is Professor and Chair, Department of Obstetrics, Gynecology and Women’s Health, and Assistant Dean, Clinical Research Unit, Rutgers New Jersey Medical School, Newark, New Jersey.
Dr. Einstein has advised or participated in educational speaking activities, but he does not receive an honorarium from any companies. In specific cases, Rutgers has received payment for his time spent for these activities from Photocure, Papivax, Cynvec, Merck, Hologic, and PDS Biotechnology. If travel is required for meetings with industry, the company pays for Dr. Einstein’s travel expenses. Rutgers has received grant funding for research-related costs of clinical trials that Dr. Einstein has been the overall or local principal investigator within the past 12 months from J&J, Pfizer, and Inovio. Rutgers has received payment for Dr. Einstein’s time from Photocure, Papivax, Cynvec, and PDS Biotechnology.
Dr. Novetsky is the overall principal investigator of an investigator-initiated grant sponsored by Roche. His institution, Rutgers, has received funding for the clinical costs of this trial.
Dr. Marcus reports no financial relationships relevant to this article.
Cervical cancer rates remain low in the United States, with the incidence having plateaued for decades. And yet, in 2019, more than 13,000 US women will be diagnosed with cervical cancer.1 Globally, in 2018 almost 600,000 women were diagnosed with cervical cancer2; it is the fourth most frequent cancer in women. This is despite the fact that we have adequate primary and secondary prevention tools available to minimize—and almost eliminate—cervical cancer. We must continue to raise the bar for preventing, screening for, and managing this disease.
Human papillomavirus (HPV) vaccines provide a highly effective primary prevention strategy, but we need to improve our ability to identify and diagnose dysplastic lesions prior to the development of cervical cancer. Highly sensitive HPV testing and cytology is a powerful secondary prevention approach that enables us to assess a woman’s risk of having precancerous cells both now and in the near future. These modalities have been very successful in decreasing the incidence of cervical cancer in the United States and other areas with organized screening programs. In low- and middle-income countries, however, access to, availability of, and performance with these modalities is not optimal. Innovative strategies and new technologies are being evaluated to overcome these limitations.
Advances in radiation and surgical technology have enabled us to vastly improve cervical cancer treatment. Women with early-stage cervical cancer are candidates for surgical management, which frequently includes a radical hysterectomy and lymph node dissection. While these surgeries traditionally have been performed via an exploratory laparotomy, minimally invasive techniques (laparoscopic and robot-assisted surgical techniques) have decreased the morbidity with these surgeries. Notable new studies have shed light on the comparative effectiveness of minimally invasive technologies and have shown us that new is not always better.
The US Preventive Services Task Force (USPSTF) recently released its updated cervical cancer screening guidelines. The suggested approach to screening differs from previous recommendations. HPV testing as a primary test (that is, HPV testing alone or followed by cytology) takes the spotlight now, according to the analysis by the Task Force.
In this Update, we highlight important studies published in the past year that address these issues.
Continue to: New tech's potential to identify high-grade...
New tech's potential to identify high-grade cervical dysplasia may be a boon to low-resource settings
Hu L, Bell D, Antani S, et al. An observational study of deep learning and automated evaluation of cervical images for cancer screening. J Natl Cancer Inst. 2019;doi:10.1093/jnci/djy225.
When cervical screening tests like cytology and HPV testing show abnormal results, colposcopy often is recommended. The goal of colposcopy is to identify the areas that might harbor a high-grade precancerous lesion or worse. The gold standard in this case, however, is histology, not colposcopic impression, as many studies have shown that colposcopy without biopsies is limited and that performance is improved with more biopsies.3,4
Visual inspection with acetic acid (VIA) is an approach used often in low-resource settings where visual impression is the gold standard. However, as with colposcopy, a visual evaluation without histology does not perform well, and often women are overtreated. Many attempts have been made with new technologies to overcome the limitations of time, cost, and workforce required for cytology and histology services. New disruptive technologies may be able to surmount human limitations and improve on not only VIA but also the need for histology.
Novel technology uses images to develop algorithm with predictive ability
In a recent observational study, Hu and colleagues used images that were collected during a large population study in Guanacaste, Costa Rica.5 More than 9,000 women were followed for up to 7 years, and cervical photographs (cervigrams) were obtained. Well-annotated histopathology results were obtained for women with abnormal screening, and 279 women had a high-grade dysplastic lesion or cancer.
Cervigrams from women with high-grade lesions and matched controls were collected, and a deep learning-based algorithm using artificial intelligence technology was developed using 70% of the images. The remaining 30% of images were used as a validation set to test the algorithm's ability to "predict" high-grade dysplasia without knowing the final result.
Findings. Termed automated visual evaluation (AVE), this new technology demonstrated a very accurate ability to identify high-grade dysplasia or worse, with an area under the curve (AUC) of 0.91 from merely a cervicogram (FIGURE). This outperformed conventional Pap smears (AUC, 0.71), liquid-based cytology (AUC, 0.79) and, surprisingly, highly sensitive HPV testing (AUC, 0.82) in women in the prime of their screening ages (>25 years of age).
Colposcopy remains the gold standard for evaluating abnormal cervical cancer screening tests in the United States. But can we do better for our patients using new technologies like AVE? If validated in large-scale trials, AVE has the potential to revolutionize cervical cancer screening in low-resource settings where follow-up and adequate histology services are limited or nonexistent. Future large studies are necessary to evaluate the role of AVE alone versus in combination with other diagnostic testing (such as HPV testing) to detect cervical lesions globally.
Continue to: Data offer persuasive evidence...
Data offer persuasive evidence to abandon minimally invasive surgery in management of early-stage cervical cancer
Melamed A, Margul DJ, Chen L, et al. Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med. 2018;379:1905-1914.
Ramirez PT, Frumovitz M, Pareja R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med. 2018;379:1895-1904.
Over the past decade, gynecologic cancer surgery has shifted from what routinely were open procedures to the adoption of minimally invasive techniques. Recently, a large, well-designed prospective study and a large retrospective study both demonstrated worse outcomes with minimally invasive radical hysterectomy (MIRH) as compared with traditional open radical abdominal hysterectomy (RAH). These 2 landmark studies, initially presented at the Society of Gynecologic Oncology's 2018 annual meeting and later published in the New England Journal of Medicine, have really affected the gynecologic oncology community.
Shorter overall survival in women who had MIRH
Melamed and colleagues conducted a large, retrospective US-based study to evaluate all-cause mortality in women with cervical cancer who underwent MIRH compared with those who had RAH.6 The authors also sought to evaluate national trends in 4-year relative survival rates after minimally invasive surgery was adopted.
The study included 2,461 women who met the inclusion criteria; 49.8% (1,225) underwent MIRH procedures and, of those, 79.8% (978) had robot-assisted laparoscopy. Most women had stage IB1 tumors (88%), and most carcinomas were squamous cell (61%); 40.6% of tumors were less than 2 cm in size. There were no differences between the 2 groups with respect to rates of positive parametria, surgical margins, and lymph node involvement. Administration of adjuvant therapy, in those who qualified, was also similar between groups.
Results. At a median follow-up of 45 months, 94 deaths occurred in the minimally invasive group and 70 in the open surgery group. The risk of death at 4 years was 9.1% in the minimally invasive group versus 5.3% in the open surgery group, with a 65% higher risk of death from any cause, which was highly statistically significant.
Prospective trial showed MIRH was associated with lower survival rates
From 2008 to 2017, Ramirez and colleagues conducted a phase 3, multicenter, randomized controlled trial to prospectively establish the noninferiority of MIRH compared with RAH.7 The study included 631 women from 33 centers. The prespecified expected disease-free survival rate was 90% at 4.5 years.
To be included as a site, centers were required to submit details from 10 minimally invasive cases as well as 2 unedited videos for review by the trial management committee. In contrast to Melamed and colleagues' retrospective study, of the 319 procedures that were classified as minimally invasive, only 15.6% were robotically assisted. Similarly, most women had stage IB1 tumors (91.9%), and most were squamous cell carcinomas (67%). There were also no differences in the postoperative pathology findings or the need for adjuvant therapy administered between groups. The median follow-up was 2.5 years.
Results. At that time there were 27 recurrences in the MIRH group and 7 in the RAH group; there were also 19 deaths after MIRH and 3 after RAH. Disease-free survival at 4.5 years was 86% with MIRH versus 96.5% with RAH. Reported 3-year disease-free survival and overall survival were also significantily lower in the minimally invasive subgroup (91.2% vs 97.1%, 93.8% vs 99.0%, respectively).
Study limitations. Criticisms of this trial are that noninferiority could not be declared; in addition, the investigators were unable to complete enrollment secondary to early enrollment termination after the data and safety monitoring board raised survival concerns.
Many argue that subgroup analyses suggest a lower risk of poor outcomes in patients with smaller tumors (<2 cm); however, it is critical to note that this study was not powered to detect these differences.
The evidence is compelling and demonstrates potentially worse disease-related outcomes using MIRH when compared to traditional RAH with respect to cervical cancer recurrence, rates of death, and disease-free and overall survival. Several hypotheses have been proposed, and future research is needed to elucidate the differences in variables responsible for the outcomes demonstrated in these studies. Although there has been no ban on robot-assisted surgical devices or traditional minimally invasive techniques, the National Comprehensive Cancer Network has updated its recommendations to include careful counseling of patients who require a surgical approach for the management of early-stage cervical cancer.
Continue to: USPSTF updated guidance on cervical cancer screening...
USPSTF updated guidance on cervical cancer screening
Melnikow J, Henderson JT, Burda BU, et al. Screening for cervical cancer with high-risk human papillomavirus testing: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2018;320:687-705.
US Preventive Services Task Force, Curry SJ, Krist AH, et al. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;320:674-686.
Past guidelines for cervical cancer screening have included testing for high-risk HPV (hrHPV) as a cotest with cytology or for triage of atypical squamous cells of undetermined significance (ASCUS) in women aged 30 to 65 years.8 The American Society for Colposcopy and Cervical Pathology and the Society of Gynecologic Oncology, with other stakeholder organizations, issued interim guidance for primary HPV testing--that is, HPV test first and, in the case of non-16/18 hrHPV types, cytology as a triage. The most recent evidence report and systematic review by Melnikow and colleagues for the USPSTF offers an in-depth analysis of risks, benefits, harms, and value of cotesting and other management strategies.9
Focus on screening effectiveness
Large trials of cotesting were conducted in women aged 25 to 65.10-13 These studies all consistently showed that primary hrHPV screening led to a statistically significant increased detection of cervical intraepithelial neoplasia (CIN) 3+ in the initial round of screening, with a relative risk of detecting CIN 3+ ranging from 1.61 to 7.46 compared with cytology alone.
Four additional studies compared cotesting with conventional cytology for the detection of CIN 3+. None of these trials demonstrated a significantly higher detection rate of CIN 3+ with cotesting compared with conventional cytology testing alone. Notably, the studies reviewed were performed in European countries that had organized screening programs in place and a nationalized health care system. Thus, these data may not be as applicable to women in the United States, particularly to women who have limited health care access.
Risks of screening
In the same studies reviewed for screening effectiveness, the investigators found that overall, screening with hrHPV primary or cotesting was associated with more false-positive results and higher colposcopy rates. Women screened with hrHPV alone had a 7.9% referral rate to colposcopy, while those screened with cytology had a 2.8% referral rate to colposcopy. Similarly, the rate of biopsy was higher in the hrHPV-only group (3.2% vs 1.3%).
Overall, while cotesting might have some improvement in performance compared with hrHPV as a single modality, there might be risks of overreferral to colposcopy and overtreatment with additional cytology over hrHPV testing alone.
This evidence review also included an analysis of more potential harms. Very limited evidence suggests that positive hrHPV test results may be associated with greater psychological harm, including decreased sexual satisfaction, increased anxiety and distress, and worse feelings about sexual partners, than abnormal cytology results. These were assessed, however, 1 to 2 weeks after the test results were provided to the patients, and long-term assessment was not done.
New recommendations from the USPSTF
Based on these data, the USPSTF issued new recommendations regarding screening (TABLE).14 For women aged 21 to 29, cytology alone should be used for screening every 3 years. Women aged 30 to 65 can be screened with cytology alone every 3 years, with hrHPV testing alone every 5 years, or with cotesting every 5 years.
Primary screening with hrHPV is more effective in diagnosing a CIN 3+ than cytology alone. Cotesting with cytology and hrHPV testing appears to have limited performance improvement, with potential harm, compared with hrHPV testing alone in diagnosing CIN 3+. The Task Force recommendation is hrHPV testing alone or cotesting every 5 years.
Cervical cancer rates remain low in the United States, with the incidence having plateaued for decades. And yet, in 2019, more than 13,000 US women will be diagnosed with cervical cancer.1 Globally, in 2018 almost 600,000 women were diagnosed with cervical cancer2; it is the fourth most frequent cancer in women. This is despite the fact that we have adequate primary and secondary prevention tools available to minimize—and almost eliminate—cervical cancer. We must continue to raise the bar for preventing, screening for, and managing this disease.
Human papillomavirus (HPV) vaccines provide a highly effective primary prevention strategy, but we need to improve our ability to identify and diagnose dysplastic lesions prior to the development of cervical cancer. Highly sensitive HPV testing and cytology is a powerful secondary prevention approach that enables us to assess a woman’s risk of having precancerous cells both now and in the near future. These modalities have been very successful in decreasing the incidence of cervical cancer in the United States and other areas with organized screening programs. In low- and middle-income countries, however, access to, availability of, and performance with these modalities is not optimal. Innovative strategies and new technologies are being evaluated to overcome these limitations.
Advances in radiation and surgical technology have enabled us to vastly improve cervical cancer treatment. Women with early-stage cervical cancer are candidates for surgical management, which frequently includes a radical hysterectomy and lymph node dissection. While these surgeries traditionally have been performed via an exploratory laparotomy, minimally invasive techniques (laparoscopic and robot-assisted surgical techniques) have decreased the morbidity with these surgeries. Notable new studies have shed light on the comparative effectiveness of minimally invasive technologies and have shown us that new is not always better.
The US Preventive Services Task Force (USPSTF) recently released its updated cervical cancer screening guidelines. The suggested approach to screening differs from previous recommendations. HPV testing as a primary test (that is, HPV testing alone or followed by cytology) takes the spotlight now, according to the analysis by the Task Force.
In this Update, we highlight important studies published in the past year that address these issues.
Continue to: New tech's potential to identify high-grade...
New tech's potential to identify high-grade cervical dysplasia may be a boon to low-resource settings
Hu L, Bell D, Antani S, et al. An observational study of deep learning and automated evaluation of cervical images for cancer screening. J Natl Cancer Inst. 2019;doi:10.1093/jnci/djy225.
When cervical screening tests like cytology and HPV testing show abnormal results, colposcopy often is recommended. The goal of colposcopy is to identify the areas that might harbor a high-grade precancerous lesion or worse. The gold standard in this case, however, is histology, not colposcopic impression, as many studies have shown that colposcopy without biopsies is limited and that performance is improved with more biopsies.3,4
Visual inspection with acetic acid (VIA) is an approach used often in low-resource settings where visual impression is the gold standard. However, as with colposcopy, a visual evaluation without histology does not perform well, and often women are overtreated. Many attempts have been made with new technologies to overcome the limitations of time, cost, and workforce required for cytology and histology services. New disruptive technologies may be able to surmount human limitations and improve on not only VIA but also the need for histology.
Novel technology uses images to develop algorithm with predictive ability
In a recent observational study, Hu and colleagues used images that were collected during a large population study in Guanacaste, Costa Rica.5 More than 9,000 women were followed for up to 7 years, and cervical photographs (cervigrams) were obtained. Well-annotated histopathology results were obtained for women with abnormal screening, and 279 women had a high-grade dysplastic lesion or cancer.
Cervigrams from women with high-grade lesions and matched controls were collected, and a deep learning-based algorithm using artificial intelligence technology was developed using 70% of the images. The remaining 30% of images were used as a validation set to test the algorithm's ability to "predict" high-grade dysplasia without knowing the final result.
Findings. Termed automated visual evaluation (AVE), this new technology demonstrated a very accurate ability to identify high-grade dysplasia or worse, with an area under the curve (AUC) of 0.91 from merely a cervicogram (FIGURE). This outperformed conventional Pap smears (AUC, 0.71), liquid-based cytology (AUC, 0.79) and, surprisingly, highly sensitive HPV testing (AUC, 0.82) in women in the prime of their screening ages (>25 years of age).
Colposcopy remains the gold standard for evaluating abnormal cervical cancer screening tests in the United States. But can we do better for our patients using new technologies like AVE? If validated in large-scale trials, AVE has the potential to revolutionize cervical cancer screening in low-resource settings where follow-up and adequate histology services are limited or nonexistent. Future large studies are necessary to evaluate the role of AVE alone versus in combination with other diagnostic testing (such as HPV testing) to detect cervical lesions globally.
Continue to: Data offer persuasive evidence...
Data offer persuasive evidence to abandon minimally invasive surgery in management of early-stage cervical cancer
Melamed A, Margul DJ, Chen L, et al. Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med. 2018;379:1905-1914.
Ramirez PT, Frumovitz M, Pareja R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med. 2018;379:1895-1904.
Over the past decade, gynecologic cancer surgery has shifted from what routinely were open procedures to the adoption of minimally invasive techniques. Recently, a large, well-designed prospective study and a large retrospective study both demonstrated worse outcomes with minimally invasive radical hysterectomy (MIRH) as compared with traditional open radical abdominal hysterectomy (RAH). These 2 landmark studies, initially presented at the Society of Gynecologic Oncology's 2018 annual meeting and later published in the New England Journal of Medicine, have really affected the gynecologic oncology community.
Shorter overall survival in women who had MIRH
Melamed and colleagues conducted a large, retrospective US-based study to evaluate all-cause mortality in women with cervical cancer who underwent MIRH compared with those who had RAH.6 The authors also sought to evaluate national trends in 4-year relative survival rates after minimally invasive surgery was adopted.
The study included 2,461 women who met the inclusion criteria; 49.8% (1,225) underwent MIRH procedures and, of those, 79.8% (978) had robot-assisted laparoscopy. Most women had stage IB1 tumors (88%), and most carcinomas were squamous cell (61%); 40.6% of tumors were less than 2 cm in size. There were no differences between the 2 groups with respect to rates of positive parametria, surgical margins, and lymph node involvement. Administration of adjuvant therapy, in those who qualified, was also similar between groups.
Results. At a median follow-up of 45 months, 94 deaths occurred in the minimally invasive group and 70 in the open surgery group. The risk of death at 4 years was 9.1% in the minimally invasive group versus 5.3% in the open surgery group, with a 65% higher risk of death from any cause, which was highly statistically significant.
Prospective trial showed MIRH was associated with lower survival rates
From 2008 to 2017, Ramirez and colleagues conducted a phase 3, multicenter, randomized controlled trial to prospectively establish the noninferiority of MIRH compared with RAH.7 The study included 631 women from 33 centers. The prespecified expected disease-free survival rate was 90% at 4.5 years.
To be included as a site, centers were required to submit details from 10 minimally invasive cases as well as 2 unedited videos for review by the trial management committee. In contrast to Melamed and colleagues' retrospective study, of the 319 procedures that were classified as minimally invasive, only 15.6% were robotically assisted. Similarly, most women had stage IB1 tumors (91.9%), and most were squamous cell carcinomas (67%). There were also no differences in the postoperative pathology findings or the need for adjuvant therapy administered between groups. The median follow-up was 2.5 years.
Results. At that time there were 27 recurrences in the MIRH group and 7 in the RAH group; there were also 19 deaths after MIRH and 3 after RAH. Disease-free survival at 4.5 years was 86% with MIRH versus 96.5% with RAH. Reported 3-year disease-free survival and overall survival were also significantily lower in the minimally invasive subgroup (91.2% vs 97.1%, 93.8% vs 99.0%, respectively).
Study limitations. Criticisms of this trial are that noninferiority could not be declared; in addition, the investigators were unable to complete enrollment secondary to early enrollment termination after the data and safety monitoring board raised survival concerns.
Many argue that subgroup analyses suggest a lower risk of poor outcomes in patients with smaller tumors (<2 cm); however, it is critical to note that this study was not powered to detect these differences.
The evidence is compelling and demonstrates potentially worse disease-related outcomes using MIRH when compared to traditional RAH with respect to cervical cancer recurrence, rates of death, and disease-free and overall survival. Several hypotheses have been proposed, and future research is needed to elucidate the differences in variables responsible for the outcomes demonstrated in these studies. Although there has been no ban on robot-assisted surgical devices or traditional minimally invasive techniques, the National Comprehensive Cancer Network has updated its recommendations to include careful counseling of patients who require a surgical approach for the management of early-stage cervical cancer.
Continue to: USPSTF updated guidance on cervical cancer screening...
USPSTF updated guidance on cervical cancer screening
Melnikow J, Henderson JT, Burda BU, et al. Screening for cervical cancer with high-risk human papillomavirus testing: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2018;320:687-705.
US Preventive Services Task Force, Curry SJ, Krist AH, et al. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;320:674-686.
Past guidelines for cervical cancer screening have included testing for high-risk HPV (hrHPV) as a cotest with cytology or for triage of atypical squamous cells of undetermined significance (ASCUS) in women aged 30 to 65 years.8 The American Society for Colposcopy and Cervical Pathology and the Society of Gynecologic Oncology, with other stakeholder organizations, issued interim guidance for primary HPV testing--that is, HPV test first and, in the case of non-16/18 hrHPV types, cytology as a triage. The most recent evidence report and systematic review by Melnikow and colleagues for the USPSTF offers an in-depth analysis of risks, benefits, harms, and value of cotesting and other management strategies.9
Focus on screening effectiveness
Large trials of cotesting were conducted in women aged 25 to 65.10-13 These studies all consistently showed that primary hrHPV screening led to a statistically significant increased detection of cervical intraepithelial neoplasia (CIN) 3+ in the initial round of screening, with a relative risk of detecting CIN 3+ ranging from 1.61 to 7.46 compared with cytology alone.
Four additional studies compared cotesting with conventional cytology for the detection of CIN 3+. None of these trials demonstrated a significantly higher detection rate of CIN 3+ with cotesting compared with conventional cytology testing alone. Notably, the studies reviewed were performed in European countries that had organized screening programs in place and a nationalized health care system. Thus, these data may not be as applicable to women in the United States, particularly to women who have limited health care access.
Risks of screening
In the same studies reviewed for screening effectiveness, the investigators found that overall, screening with hrHPV primary or cotesting was associated with more false-positive results and higher colposcopy rates. Women screened with hrHPV alone had a 7.9% referral rate to colposcopy, while those screened with cytology had a 2.8% referral rate to colposcopy. Similarly, the rate of biopsy was higher in the hrHPV-only group (3.2% vs 1.3%).
Overall, while cotesting might have some improvement in performance compared with hrHPV as a single modality, there might be risks of overreferral to colposcopy and overtreatment with additional cytology over hrHPV testing alone.
This evidence review also included an analysis of more potential harms. Very limited evidence suggests that positive hrHPV test results may be associated with greater psychological harm, including decreased sexual satisfaction, increased anxiety and distress, and worse feelings about sexual partners, than abnormal cytology results. These were assessed, however, 1 to 2 weeks after the test results were provided to the patients, and long-term assessment was not done.
New recommendations from the USPSTF
Based on these data, the USPSTF issued new recommendations regarding screening (TABLE).14 For women aged 21 to 29, cytology alone should be used for screening every 3 years. Women aged 30 to 65 can be screened with cytology alone every 3 years, with hrHPV testing alone every 5 years, or with cotesting every 5 years.
Primary screening with hrHPV is more effective in diagnosing a CIN 3+ than cytology alone. Cotesting with cytology and hrHPV testing appears to have limited performance improvement, with potential harm, compared with hrHPV testing alone in diagnosing CIN 3+. The Task Force recommendation is hrHPV testing alone or cotesting every 5 years.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7-34.
- World Health Organization website. Cervical cancer. https://www.who.int/cancer/prevention/diagnosis-screening/cervical-cancer/en/. Accessed April 17, 2019.
- Wentzensen N, Walker JL, Gold MA, et al. Multiple biopsies and detection of cervical cancer precursors at colposcopy. J Clin Oncol. 2015;33:83-89.
- Gage JC, Hanson VW, Abbey K, et al. Number of cervical biopsies and sensitivity of colposcopy. Obstet Gynecol. 2006;108:264-272.
- Hu L, Bell D, Antani S, et al. An observational study of deep learning and automated evaluation of cervical images for cancer screening. J Natl Cancer Inst. 2019;doi:10.1093/jnci/djy225.
- Melamed A, Margul DJ, Chen L, et al. Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med. 2018;379:1905-1914.
- Ramirez PT, Frumovitz M, Pareja R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med. 2018;379:1895-1904.
- Saslow D, Solomon D, Lawson HW, et al; ACS-ASCCP-ASCP Cervical Cancer Guideline Committee. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA Cancer J Clin. 2012;62:147-172.
- Melnikow J, Henderson JT, Burda BU, et al. Screening for cervical cancer with high-risk human papillomavirus testing: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2018;320:687-705.
- Canfell K, Caruana M, Gebski V, et al. Cervical screening with primary HPV testing or cytology in a population of women in which those aged 33 years or younger had previously been offered HPV vaccination: results of the Compass pilot randomised trial. PLoS Med. 2017;14:e1002388. doi:10.1371/journal.pmed.1002388.
- Leinonen MK, Nieminen P, Lonnberg S, et al. Detection rates of precancerous and cancerous cervical lesions within one screening round of primary human papillomavirus DNA testing: prospective randomised trial in Finland. BMJ. 2012;345:e7789.
- Ogilvie GS, van Niekerk D, Krajden M, et al. Effect of screening with primary cervical HPV testing vs cytology testing on high-grade cervical intraepithelial neoplasia at 48 months: the HPV FOCAL randomized clinical trial. JAMA. 2018;320:43-52.
- Ronco G, Fioprgi-Rossi P, Carozzi F, et al; New Technologies for Cervical Cancer screening (NTCC) Working Group. Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial. Lancet Oncol. 2010;11:249-257.
- US Preventive Services Task Force, Curry SJ, Krist AH, et al. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;320:674-686.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7-34.
- World Health Organization website. Cervical cancer. https://www.who.int/cancer/prevention/diagnosis-screening/cervical-cancer/en/. Accessed April 17, 2019.
- Wentzensen N, Walker JL, Gold MA, et al. Multiple biopsies and detection of cervical cancer precursors at colposcopy. J Clin Oncol. 2015;33:83-89.
- Gage JC, Hanson VW, Abbey K, et al. Number of cervical biopsies and sensitivity of colposcopy. Obstet Gynecol. 2006;108:264-272.
- Hu L, Bell D, Antani S, et al. An observational study of deep learning and automated evaluation of cervical images for cancer screening. J Natl Cancer Inst. 2019;doi:10.1093/jnci/djy225.
- Melamed A, Margul DJ, Chen L, et al. Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med. 2018;379:1905-1914.
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