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Authors of picosecond laser review predict more widespread use of the technology
Ever since the first picosecond laser hit the market in 2012 as an option for treating unwanted tattoos and pigmented lesions, clinicians have used the technology to safely and effectively treat an expanding range of dermatologic conditions, from Nevus of Ota and melasma to rejuvenation.
. They called for further development of the technology and predicted that application of the devices will become more widespread.
“Future directions may include the development of even shorter pulse durations, improvements in fractionation method and delivery, and exploration of the utility of pulsing other laser wavelengths in the picosecond (or shorter) domain,” first author Douglas C. Wu, MD, PhD, of Cosmetic Laser Dermatology and colleagues wrote in the review. “The introduction of newer devices along with continued improvements in clinical technique and experience will drive the refinement and expansion of this technology.”
The authors evaluated medical literature on the topic published up to March 2020 and classified 78 studies into one of the following categories: discrete pigmented lesions, other nonmelasma pigmented conditions, rejuvenation, melasma, scar revision, and tattoo removal. They assessed the level of evidence for each indication according to modified criteria published by the Oxford Centre of Evidence-Based Medicine and proposed recommendations based on the medical literature in combination with the authors’ collective clinical experience with picosecond laser.
In the category of discrete pigmented lesions, the authors assigned level of evidence 1a to Nevus of Ota and Hori’s macules, level of evidence 2b to solar lentigines and freckles, level of evidence 3c to café au lait macules, and level of evidence 4 to all other benign pigmentary conditions. “Comparative studies utilizing clinical, histological, and microscopic endpoints further suggest that picosecond laser may be safer and more effective than nanosecond laser in some situations, with potentially reduced risk of inducing postinflammatory hyperpigmentation,” the authors wrote. “This increased safety level may be due to the reduction of non-specific photothermal damage of the melanocyte and dermal-epidermal junction,” they noted. They called for more robust clinical comparative data with a focus on shorter pulse durations and refined clinical endpoints “to further distinguish the differences between picosecond and nanosecond laser for the treatment of some benign pigmented lesions.”
Based on seven prospective open-label trials and three split-face comparison trials involving the use of picosecond lasers for photorejuvenation, the authors assigned a level of evidence 2a to this category. “The studies show a high level of safety associated with a moderate level of efficacy,” they wrote. “Indeed, when compared with traditional non-ablative fractional laser, fractionated picosecond laser may have an improved side effect profile without sacrificing treatment efficacy. This could be due to the unique mechanism of action of fractionated picosecond laser, which results in greater confinement of tissue injury to focal and precise points within the epidermis and papillary dermis.”
Clinical data on using picosecond lasers to treat melasma remains “mixed and unclear,” but it may have a role as an adjunctive treatment combined with rigorous photoprotection, topical melanin inhibitors, “and potentially other laser or systemic therapies as dictated by clinical circumstance,” the authors said. They do not recommend the picosecond laser as a monotherapy for melasma, and they assigned a level of evidence 2a to this category.
Although the fractionated picosecond laser is cleared by the Food and Drug Administration for the treatment of acne scars, Dr. Wu and his colleagues noted that rigorous clinical data on using the technology for this indication is limited. “Encouragingly, reports thus far seem to suggest that the risk of post-inflammatory pigmentary alteration is low when using fractionated picosecond laser, which has added significance due to the high prevalence of acne scarring in skin of color,” they wrote. They assigned a level of evidence 2b to this category. Meanwhile, clinical data on the use of picosecond lasers for non-acne scars are limited to cases series and retrospective reviews, reaching evidence level 3c. “Although the level of evidence is weak, there is likely an effective role for fractionated picosecond laser for the improvement of hyperpigmented scars given its more robust track record for the treatment of hyperpigmentation due to other causes such as benign pigmentary conditions and photodamage,” the authors wrote.
The manuscript concludes with a discussion of the picosecond laser’s role in tattoo removal, which represents the oldest and most established dermatologic indication for the technology. “The accumulated scientific and clinical evidence to date concludes that the shorter pulse duration confers a distinct advantage when other laser parameters remain equal,” the authors wrote. “The evidence also suggests that the shorter the pulse gets (within currently commercially available and tested devices), the greater becomes the efficacy for tattoo removal. There is no evidence to suggest that larger tattoo particles are more optimally targeted by longer nanosecond pulses.” They assigned a level of evidence 1a to this category and described using the picosecond laser for tattoo removal of almost any color as “the gold standard.”
In an interview, Arisa Ortiz, MD, described the manuscript as a thorough review of the clinical indications for picosecond lasers. “Overall, the review shows evidence for slightly better improvement of efficacy with picosecond lasers compared to nanosecond lasers,” said Dr. Ortiz, director of laser and cosmetic dermatology at the University of California, San Diego, who was not involved with the review. “They also show a slightly improved side effect profile with picosecond lasers [and] notably, less risk of postinflammatory hyperpigmentation in darker skin types compared to nanosecond lasers. One issue that was not addressed was the cost of picosecond lasers. The cost of a picosecond lasers remains substantially higher than the cost of a nanosecond laser. I am not sure that this extra cost justifies a slightly improved efficacy or slightly improved side effect profile.”
According to Eric F. Bernstein, MD, director of the Main Line Center for Laser Surgery in Ardmore, Penn., the versatility of picosecond lasers offers an advantage to dermatologists. “Most of them have three wavelengths at least,” said Dr. Bernstein, who was not involved with the systematic review. “That means you can treat skin types I-VI. I was never able to offer much for my patients with skin types V and VI for fractionated rejuvenation and treatment of acne scarring. But now, with these lasers, I have an option for them. That’s a huge advantage.”
He credited laser engineers as “the real heroes” in the success of picosecond lasers in dermatology. “They’re passionate, they’re brilliant, and they’re creative,” Dr. Bernstein said. “They’re the ones that build and produce these devices for multiple manufacturers. In our space, the innovation really comes from industry.”
The review authors and Dr. Ortiz reported having no relevant disclosures. Dr. Bernstein disclosed that he is head of Candela’s medical advisory board.
SOURCE: Wu DC et al. Lasers Surg Med. 2020. doi: 10.1002/lsm.23244.
Ever since the first picosecond laser hit the market in 2012 as an option for treating unwanted tattoos and pigmented lesions, clinicians have used the technology to safely and effectively treat an expanding range of dermatologic conditions, from Nevus of Ota and melasma to rejuvenation.
. They called for further development of the technology and predicted that application of the devices will become more widespread.
“Future directions may include the development of even shorter pulse durations, improvements in fractionation method and delivery, and exploration of the utility of pulsing other laser wavelengths in the picosecond (or shorter) domain,” first author Douglas C. Wu, MD, PhD, of Cosmetic Laser Dermatology and colleagues wrote in the review. “The introduction of newer devices along with continued improvements in clinical technique and experience will drive the refinement and expansion of this technology.”
The authors evaluated medical literature on the topic published up to March 2020 and classified 78 studies into one of the following categories: discrete pigmented lesions, other nonmelasma pigmented conditions, rejuvenation, melasma, scar revision, and tattoo removal. They assessed the level of evidence for each indication according to modified criteria published by the Oxford Centre of Evidence-Based Medicine and proposed recommendations based on the medical literature in combination with the authors’ collective clinical experience with picosecond laser.
In the category of discrete pigmented lesions, the authors assigned level of evidence 1a to Nevus of Ota and Hori’s macules, level of evidence 2b to solar lentigines and freckles, level of evidence 3c to café au lait macules, and level of evidence 4 to all other benign pigmentary conditions. “Comparative studies utilizing clinical, histological, and microscopic endpoints further suggest that picosecond laser may be safer and more effective than nanosecond laser in some situations, with potentially reduced risk of inducing postinflammatory hyperpigmentation,” the authors wrote. “This increased safety level may be due to the reduction of non-specific photothermal damage of the melanocyte and dermal-epidermal junction,” they noted. They called for more robust clinical comparative data with a focus on shorter pulse durations and refined clinical endpoints “to further distinguish the differences between picosecond and nanosecond laser for the treatment of some benign pigmented lesions.”
Based on seven prospective open-label trials and three split-face comparison trials involving the use of picosecond lasers for photorejuvenation, the authors assigned a level of evidence 2a to this category. “The studies show a high level of safety associated with a moderate level of efficacy,” they wrote. “Indeed, when compared with traditional non-ablative fractional laser, fractionated picosecond laser may have an improved side effect profile without sacrificing treatment efficacy. This could be due to the unique mechanism of action of fractionated picosecond laser, which results in greater confinement of tissue injury to focal and precise points within the epidermis and papillary dermis.”
Clinical data on using picosecond lasers to treat melasma remains “mixed and unclear,” but it may have a role as an adjunctive treatment combined with rigorous photoprotection, topical melanin inhibitors, “and potentially other laser or systemic therapies as dictated by clinical circumstance,” the authors said. They do not recommend the picosecond laser as a monotherapy for melasma, and they assigned a level of evidence 2a to this category.
Although the fractionated picosecond laser is cleared by the Food and Drug Administration for the treatment of acne scars, Dr. Wu and his colleagues noted that rigorous clinical data on using the technology for this indication is limited. “Encouragingly, reports thus far seem to suggest that the risk of post-inflammatory pigmentary alteration is low when using fractionated picosecond laser, which has added significance due to the high prevalence of acne scarring in skin of color,” they wrote. They assigned a level of evidence 2b to this category. Meanwhile, clinical data on the use of picosecond lasers for non-acne scars are limited to cases series and retrospective reviews, reaching evidence level 3c. “Although the level of evidence is weak, there is likely an effective role for fractionated picosecond laser for the improvement of hyperpigmented scars given its more robust track record for the treatment of hyperpigmentation due to other causes such as benign pigmentary conditions and photodamage,” the authors wrote.
The manuscript concludes with a discussion of the picosecond laser’s role in tattoo removal, which represents the oldest and most established dermatologic indication for the technology. “The accumulated scientific and clinical evidence to date concludes that the shorter pulse duration confers a distinct advantage when other laser parameters remain equal,” the authors wrote. “The evidence also suggests that the shorter the pulse gets (within currently commercially available and tested devices), the greater becomes the efficacy for tattoo removal. There is no evidence to suggest that larger tattoo particles are more optimally targeted by longer nanosecond pulses.” They assigned a level of evidence 1a to this category and described using the picosecond laser for tattoo removal of almost any color as “the gold standard.”
In an interview, Arisa Ortiz, MD, described the manuscript as a thorough review of the clinical indications for picosecond lasers. “Overall, the review shows evidence for slightly better improvement of efficacy with picosecond lasers compared to nanosecond lasers,” said Dr. Ortiz, director of laser and cosmetic dermatology at the University of California, San Diego, who was not involved with the review. “They also show a slightly improved side effect profile with picosecond lasers [and] notably, less risk of postinflammatory hyperpigmentation in darker skin types compared to nanosecond lasers. One issue that was not addressed was the cost of picosecond lasers. The cost of a picosecond lasers remains substantially higher than the cost of a nanosecond laser. I am not sure that this extra cost justifies a slightly improved efficacy or slightly improved side effect profile.”
According to Eric F. Bernstein, MD, director of the Main Line Center for Laser Surgery in Ardmore, Penn., the versatility of picosecond lasers offers an advantage to dermatologists. “Most of them have three wavelengths at least,” said Dr. Bernstein, who was not involved with the systematic review. “That means you can treat skin types I-VI. I was never able to offer much for my patients with skin types V and VI for fractionated rejuvenation and treatment of acne scarring. But now, with these lasers, I have an option for them. That’s a huge advantage.”
He credited laser engineers as “the real heroes” in the success of picosecond lasers in dermatology. “They’re passionate, they’re brilliant, and they’re creative,” Dr. Bernstein said. “They’re the ones that build and produce these devices for multiple manufacturers. In our space, the innovation really comes from industry.”
The review authors and Dr. Ortiz reported having no relevant disclosures. Dr. Bernstein disclosed that he is head of Candela’s medical advisory board.
SOURCE: Wu DC et al. Lasers Surg Med. 2020. doi: 10.1002/lsm.23244.
Ever since the first picosecond laser hit the market in 2012 as an option for treating unwanted tattoos and pigmented lesions, clinicians have used the technology to safely and effectively treat an expanding range of dermatologic conditions, from Nevus of Ota and melasma to rejuvenation.
. They called for further development of the technology and predicted that application of the devices will become more widespread.
“Future directions may include the development of even shorter pulse durations, improvements in fractionation method and delivery, and exploration of the utility of pulsing other laser wavelengths in the picosecond (or shorter) domain,” first author Douglas C. Wu, MD, PhD, of Cosmetic Laser Dermatology and colleagues wrote in the review. “The introduction of newer devices along with continued improvements in clinical technique and experience will drive the refinement and expansion of this technology.”
The authors evaluated medical literature on the topic published up to March 2020 and classified 78 studies into one of the following categories: discrete pigmented lesions, other nonmelasma pigmented conditions, rejuvenation, melasma, scar revision, and tattoo removal. They assessed the level of evidence for each indication according to modified criteria published by the Oxford Centre of Evidence-Based Medicine and proposed recommendations based on the medical literature in combination with the authors’ collective clinical experience with picosecond laser.
In the category of discrete pigmented lesions, the authors assigned level of evidence 1a to Nevus of Ota and Hori’s macules, level of evidence 2b to solar lentigines and freckles, level of evidence 3c to café au lait macules, and level of evidence 4 to all other benign pigmentary conditions. “Comparative studies utilizing clinical, histological, and microscopic endpoints further suggest that picosecond laser may be safer and more effective than nanosecond laser in some situations, with potentially reduced risk of inducing postinflammatory hyperpigmentation,” the authors wrote. “This increased safety level may be due to the reduction of non-specific photothermal damage of the melanocyte and dermal-epidermal junction,” they noted. They called for more robust clinical comparative data with a focus on shorter pulse durations and refined clinical endpoints “to further distinguish the differences between picosecond and nanosecond laser for the treatment of some benign pigmented lesions.”
Based on seven prospective open-label trials and three split-face comparison trials involving the use of picosecond lasers for photorejuvenation, the authors assigned a level of evidence 2a to this category. “The studies show a high level of safety associated with a moderate level of efficacy,” they wrote. “Indeed, when compared with traditional non-ablative fractional laser, fractionated picosecond laser may have an improved side effect profile without sacrificing treatment efficacy. This could be due to the unique mechanism of action of fractionated picosecond laser, which results in greater confinement of tissue injury to focal and precise points within the epidermis and papillary dermis.”
Clinical data on using picosecond lasers to treat melasma remains “mixed and unclear,” but it may have a role as an adjunctive treatment combined with rigorous photoprotection, topical melanin inhibitors, “and potentially other laser or systemic therapies as dictated by clinical circumstance,” the authors said. They do not recommend the picosecond laser as a monotherapy for melasma, and they assigned a level of evidence 2a to this category.
Although the fractionated picosecond laser is cleared by the Food and Drug Administration for the treatment of acne scars, Dr. Wu and his colleagues noted that rigorous clinical data on using the technology for this indication is limited. “Encouragingly, reports thus far seem to suggest that the risk of post-inflammatory pigmentary alteration is low when using fractionated picosecond laser, which has added significance due to the high prevalence of acne scarring in skin of color,” they wrote. They assigned a level of evidence 2b to this category. Meanwhile, clinical data on the use of picosecond lasers for non-acne scars are limited to cases series and retrospective reviews, reaching evidence level 3c. “Although the level of evidence is weak, there is likely an effective role for fractionated picosecond laser for the improvement of hyperpigmented scars given its more robust track record for the treatment of hyperpigmentation due to other causes such as benign pigmentary conditions and photodamage,” the authors wrote.
The manuscript concludes with a discussion of the picosecond laser’s role in tattoo removal, which represents the oldest and most established dermatologic indication for the technology. “The accumulated scientific and clinical evidence to date concludes that the shorter pulse duration confers a distinct advantage when other laser parameters remain equal,” the authors wrote. “The evidence also suggests that the shorter the pulse gets (within currently commercially available and tested devices), the greater becomes the efficacy for tattoo removal. There is no evidence to suggest that larger tattoo particles are more optimally targeted by longer nanosecond pulses.” They assigned a level of evidence 1a to this category and described using the picosecond laser for tattoo removal of almost any color as “the gold standard.”
In an interview, Arisa Ortiz, MD, described the manuscript as a thorough review of the clinical indications for picosecond lasers. “Overall, the review shows evidence for slightly better improvement of efficacy with picosecond lasers compared to nanosecond lasers,” said Dr. Ortiz, director of laser and cosmetic dermatology at the University of California, San Diego, who was not involved with the review. “They also show a slightly improved side effect profile with picosecond lasers [and] notably, less risk of postinflammatory hyperpigmentation in darker skin types compared to nanosecond lasers. One issue that was not addressed was the cost of picosecond lasers. The cost of a picosecond lasers remains substantially higher than the cost of a nanosecond laser. I am not sure that this extra cost justifies a slightly improved efficacy or slightly improved side effect profile.”
According to Eric F. Bernstein, MD, director of the Main Line Center for Laser Surgery in Ardmore, Penn., the versatility of picosecond lasers offers an advantage to dermatologists. “Most of them have three wavelengths at least,” said Dr. Bernstein, who was not involved with the systematic review. “That means you can treat skin types I-VI. I was never able to offer much for my patients with skin types V and VI for fractionated rejuvenation and treatment of acne scarring. But now, with these lasers, I have an option for them. That’s a huge advantage.”
He credited laser engineers as “the real heroes” in the success of picosecond lasers in dermatology. “They’re passionate, they’re brilliant, and they’re creative,” Dr. Bernstein said. “They’re the ones that build and produce these devices for multiple manufacturers. In our space, the innovation really comes from industry.”
The review authors and Dr. Ortiz reported having no relevant disclosures. Dr. Bernstein disclosed that he is head of Candela’s medical advisory board.
SOURCE: Wu DC et al. Lasers Surg Med. 2020. doi: 10.1002/lsm.23244.
FROM LASERS IN SURGERY AND MEDICINE
Oral relugolix works to a T against advanced prostate cancer
according to investigators from the phase 3 HERO trial.
Relugolix was also associated with a significantly lower incidence of major adverse cardiovascular events (MACE), reported Neal D. Shore, MD, of the Carolina Urologic Research Center in Myrtle Beach, S.C., in a presentation made as a part of the American Society of Clinical Oncology virtual scientific program. The study was published simultaneously in The New England Journal of Medicine.
“Relugolix is a novel oral GnRH antagonist that has the potential to become a new standard for ADT [androgen-deprivation therapy] in advanced prostate cancer,” Dr. Shore said. He added that a potential advantage of relugolix compared with the leutenizing hormone-releasing hormone (LHRH) agonist leuprolide is the oral agent’s adverse event profile.
“Of note, and importantly, cardiovascular mortality is the leading cause of death for patients with prostate cancer. The percentage of patients with prostate cancer dying of cardiovascular disease has surpassed the percentage of patients dying from prostate cancer itself since the early 1990s. Approximately 30% of men with prostate cancer have known cardiovascular disease, and many more of these patients have comorbid risk factors, including obesity, diabetes, hypertension, and hyperlipidemia,” Dr. Shore said.
LHRH agonists also cause an initial testosterone surge that may cause an early but transient symptom flare. In contrast, relugolix has a direct inhibitory effect on pituitary GnRH receptors, leading to suppression of both leutenizing hormone and follicle-stimulating hormone, with no testosterone flare.
Study details
In the HERO trial, men with advanced prostate cancer were randomized in a 2:1 ratio to receive either relugolix at a 360-mg loading dose on day 1 followed by a 120-mg oral dose once daily (n = 622) or leuprolide delivered via depot injection every 3 months (n = 308) for a total of 48 weeks.
About half of all patients in each arm had biochemical (prostate-specific antigen, or “PSA”) relapse, 23% had newly diagnosed androgen-sensitive metastatic disease, and the remaining men (26%-28%) had advanced localized disease.
Patients with a history of a MACE event – a composite of nonfatal myocardial infarction, nonfatal stroke, and death from any cause – within 6 months were excluded.
The median PSA level at baseline was 11.7 mg/mL in the relugolix arm and 9.4 ng/mL in the leuprolide arm. Respective median testosterone levels were 415.8 ng/dL and 395.9 ng/dL.
“Of note, more than 90% of men enrolled in this study had at least one cardiovascular risk factor,” Dr. Shore said. “Tobacco use and obesity were common, as were diabetes and hypertension. Fourteen percent of men reported a prior history of major adverse cardiovascular event, such as a heart attack or stroke; this is lower than the 30% expected in a typical population of men with advanced prostate cancer given the study’s cardiovascular exclusion criteria.”
Efficacy
Sustained testosterone suppression to castration levels (less than 50 ng/dL) was achieved through 48 weeks in 96.7% of patients on relugolix, compared with 88.8% of men on leuprolide.
The absolute difference of 7.9% reached the statistical definitions for both noninferiority and superiority of relugolix over leuprolide (P for superiority < .001).
Mean testosterone levels on day 4 had decreased to below 50 ng/dL for relugolix and were maintained at castration levels until the end of treatment. In the leuprolide group, the mean testosterone level on day 4 was 625 ng/dL, which declined to castration levels by day 29 and remained below 50 ng/dL after the end of treatment at week 53. In contrast, testosterone levels in the relugolix arm began to recover immediately after the cessation of therapy.
Results with relugolix were significantly better than with leuprolide for the following endpoints (P < .0001 for all comparisons):
- Proportion of patients with PSA response at day 15 and confirmed at day 29 (79.4% vs. 19.8%)
- Cumulative probability of testosterone suppression to less than 50 ng/dL on day 15 (98.7% vs. 12.05%)
- Cumulative probability of profound testosterone suppression to less than 20 ng/dL on day 15 (78.38% vs. 0.98%)
- Mean follicle-stimulating hormone level at the end of week 24 (1.72 vs. 5.95 IU/L).
Safety
Treatment-related adverse events occurred in 73.6% of patients treated with relugolix and 68.8% of those who received leuprolide. Grade 3 or greater adverse events occurred in 3.4% and 2.6%, respectively. The respective incidences of fatal adverse events were 1.1% and 2.9%.
At 48 weeks, MACE had occurred in 2.9% of patients on relugolix and 6.2% on leuprolide. Among men with a history of a MACE event more than 6 months before study entry, leuprolide was associated with a nearly sixfold increased risk for a new MACE.
The investigators also found that compliance with the assigned medication was greater than 99% in each study arm, allaying concerns that men assigned to the oral therapy might be less likely to faithfully take their medicine.
Antagonists vs. agonists
Agents such as relugolix, which are, in effect, LHRH antagonists, have several advantages over LHRH agonists, according to invited discussant Elahe Mostaghel, MD, PhD, of the VA Puget Sound Health Care System and Fred Hutchinson Cancer Research Center, both in Seattle.
“Cost and access aside, antagonists have potential benefits over agonists, each of which may be more or less important, depending on context,” she said.
Antagonists have a more rapid onset of castration, lack the flare response seen with agonists such as leuprolide, and are associated with a significant decrease in risk for MACE.
“Differences in depth and consistency of androgen suppression may also be important. LHRH antagonists may be superior to LHRH agonists in this regard, although this remains to be fully proven, while rapid testosterone recovery and oral administration may also have benefits in particular contexts,” Dr. Mostaghel said.
“It is likely that the anticancer effects of a GnRH antagonist will not be inferior to those of a GnRH agonist and may be beneficial in terms of cardiovascular events that may be life-limiting,” Celestia S. Higano, MD, of the University of Washington in Seattle wrote in an editorial accompanying the HERO study in The New England Journal of Medicine.
“Close monitoring will be required because exposure to oral relugolix for longer than 48 weeks has not been studied and many oral agents are associated with adherence problems, especially if they cause adverse effects,” Dr. Higano added.
The HERO study was supported by Myovant. Dr. Shore disclosed relationships with Myovant and other companies. Dr. Mostaghel disclosed affiliations with Context Therapeutics. Dr. Hinago disclosed grants and fees from various companies, not including Myovant.
SOURCES: Shore ND et al. ASCO 2020, Abstract 5602; N Engl J Med. 2020 May 29. doi: 10.1056/NEJMoa2004325.
according to investigators from the phase 3 HERO trial.
Relugolix was also associated with a significantly lower incidence of major adverse cardiovascular events (MACE), reported Neal D. Shore, MD, of the Carolina Urologic Research Center in Myrtle Beach, S.C., in a presentation made as a part of the American Society of Clinical Oncology virtual scientific program. The study was published simultaneously in The New England Journal of Medicine.
“Relugolix is a novel oral GnRH antagonist that has the potential to become a new standard for ADT [androgen-deprivation therapy] in advanced prostate cancer,” Dr. Shore said. He added that a potential advantage of relugolix compared with the leutenizing hormone-releasing hormone (LHRH) agonist leuprolide is the oral agent’s adverse event profile.
“Of note, and importantly, cardiovascular mortality is the leading cause of death for patients with prostate cancer. The percentage of patients with prostate cancer dying of cardiovascular disease has surpassed the percentage of patients dying from prostate cancer itself since the early 1990s. Approximately 30% of men with prostate cancer have known cardiovascular disease, and many more of these patients have comorbid risk factors, including obesity, diabetes, hypertension, and hyperlipidemia,” Dr. Shore said.
LHRH agonists also cause an initial testosterone surge that may cause an early but transient symptom flare. In contrast, relugolix has a direct inhibitory effect on pituitary GnRH receptors, leading to suppression of both leutenizing hormone and follicle-stimulating hormone, with no testosterone flare.
Study details
In the HERO trial, men with advanced prostate cancer were randomized in a 2:1 ratio to receive either relugolix at a 360-mg loading dose on day 1 followed by a 120-mg oral dose once daily (n = 622) or leuprolide delivered via depot injection every 3 months (n = 308) for a total of 48 weeks.
About half of all patients in each arm had biochemical (prostate-specific antigen, or “PSA”) relapse, 23% had newly diagnosed androgen-sensitive metastatic disease, and the remaining men (26%-28%) had advanced localized disease.
Patients with a history of a MACE event – a composite of nonfatal myocardial infarction, nonfatal stroke, and death from any cause – within 6 months were excluded.
The median PSA level at baseline was 11.7 mg/mL in the relugolix arm and 9.4 ng/mL in the leuprolide arm. Respective median testosterone levels were 415.8 ng/dL and 395.9 ng/dL.
“Of note, more than 90% of men enrolled in this study had at least one cardiovascular risk factor,” Dr. Shore said. “Tobacco use and obesity were common, as were diabetes and hypertension. Fourteen percent of men reported a prior history of major adverse cardiovascular event, such as a heart attack or stroke; this is lower than the 30% expected in a typical population of men with advanced prostate cancer given the study’s cardiovascular exclusion criteria.”
Efficacy
Sustained testosterone suppression to castration levels (less than 50 ng/dL) was achieved through 48 weeks in 96.7% of patients on relugolix, compared with 88.8% of men on leuprolide.
The absolute difference of 7.9% reached the statistical definitions for both noninferiority and superiority of relugolix over leuprolide (P for superiority < .001).
Mean testosterone levels on day 4 had decreased to below 50 ng/dL for relugolix and were maintained at castration levels until the end of treatment. In the leuprolide group, the mean testosterone level on day 4 was 625 ng/dL, which declined to castration levels by day 29 and remained below 50 ng/dL after the end of treatment at week 53. In contrast, testosterone levels in the relugolix arm began to recover immediately after the cessation of therapy.
Results with relugolix were significantly better than with leuprolide for the following endpoints (P < .0001 for all comparisons):
- Proportion of patients with PSA response at day 15 and confirmed at day 29 (79.4% vs. 19.8%)
- Cumulative probability of testosterone suppression to less than 50 ng/dL on day 15 (98.7% vs. 12.05%)
- Cumulative probability of profound testosterone suppression to less than 20 ng/dL on day 15 (78.38% vs. 0.98%)
- Mean follicle-stimulating hormone level at the end of week 24 (1.72 vs. 5.95 IU/L).
Safety
Treatment-related adverse events occurred in 73.6% of patients treated with relugolix and 68.8% of those who received leuprolide. Grade 3 or greater adverse events occurred in 3.4% and 2.6%, respectively. The respective incidences of fatal adverse events were 1.1% and 2.9%.
At 48 weeks, MACE had occurred in 2.9% of patients on relugolix and 6.2% on leuprolide. Among men with a history of a MACE event more than 6 months before study entry, leuprolide was associated with a nearly sixfold increased risk for a new MACE.
The investigators also found that compliance with the assigned medication was greater than 99% in each study arm, allaying concerns that men assigned to the oral therapy might be less likely to faithfully take their medicine.
Antagonists vs. agonists
Agents such as relugolix, which are, in effect, LHRH antagonists, have several advantages over LHRH agonists, according to invited discussant Elahe Mostaghel, MD, PhD, of the VA Puget Sound Health Care System and Fred Hutchinson Cancer Research Center, both in Seattle.
“Cost and access aside, antagonists have potential benefits over agonists, each of which may be more or less important, depending on context,” she said.
Antagonists have a more rapid onset of castration, lack the flare response seen with agonists such as leuprolide, and are associated with a significant decrease in risk for MACE.
“Differences in depth and consistency of androgen suppression may also be important. LHRH antagonists may be superior to LHRH agonists in this regard, although this remains to be fully proven, while rapid testosterone recovery and oral administration may also have benefits in particular contexts,” Dr. Mostaghel said.
“It is likely that the anticancer effects of a GnRH antagonist will not be inferior to those of a GnRH agonist and may be beneficial in terms of cardiovascular events that may be life-limiting,” Celestia S. Higano, MD, of the University of Washington in Seattle wrote in an editorial accompanying the HERO study in The New England Journal of Medicine.
“Close monitoring will be required because exposure to oral relugolix for longer than 48 weeks has not been studied and many oral agents are associated with adherence problems, especially if they cause adverse effects,” Dr. Higano added.
The HERO study was supported by Myovant. Dr. Shore disclosed relationships with Myovant and other companies. Dr. Mostaghel disclosed affiliations with Context Therapeutics. Dr. Hinago disclosed grants and fees from various companies, not including Myovant.
SOURCES: Shore ND et al. ASCO 2020, Abstract 5602; N Engl J Med. 2020 May 29. doi: 10.1056/NEJMoa2004325.
according to investigators from the phase 3 HERO trial.
Relugolix was also associated with a significantly lower incidence of major adverse cardiovascular events (MACE), reported Neal D. Shore, MD, of the Carolina Urologic Research Center in Myrtle Beach, S.C., in a presentation made as a part of the American Society of Clinical Oncology virtual scientific program. The study was published simultaneously in The New England Journal of Medicine.
“Relugolix is a novel oral GnRH antagonist that has the potential to become a new standard for ADT [androgen-deprivation therapy] in advanced prostate cancer,” Dr. Shore said. He added that a potential advantage of relugolix compared with the leutenizing hormone-releasing hormone (LHRH) agonist leuprolide is the oral agent’s adverse event profile.
“Of note, and importantly, cardiovascular mortality is the leading cause of death for patients with prostate cancer. The percentage of patients with prostate cancer dying of cardiovascular disease has surpassed the percentage of patients dying from prostate cancer itself since the early 1990s. Approximately 30% of men with prostate cancer have known cardiovascular disease, and many more of these patients have comorbid risk factors, including obesity, diabetes, hypertension, and hyperlipidemia,” Dr. Shore said.
LHRH agonists also cause an initial testosterone surge that may cause an early but transient symptom flare. In contrast, relugolix has a direct inhibitory effect on pituitary GnRH receptors, leading to suppression of both leutenizing hormone and follicle-stimulating hormone, with no testosterone flare.
Study details
In the HERO trial, men with advanced prostate cancer were randomized in a 2:1 ratio to receive either relugolix at a 360-mg loading dose on day 1 followed by a 120-mg oral dose once daily (n = 622) or leuprolide delivered via depot injection every 3 months (n = 308) for a total of 48 weeks.
About half of all patients in each arm had biochemical (prostate-specific antigen, or “PSA”) relapse, 23% had newly diagnosed androgen-sensitive metastatic disease, and the remaining men (26%-28%) had advanced localized disease.
Patients with a history of a MACE event – a composite of nonfatal myocardial infarction, nonfatal stroke, and death from any cause – within 6 months were excluded.
The median PSA level at baseline was 11.7 mg/mL in the relugolix arm and 9.4 ng/mL in the leuprolide arm. Respective median testosterone levels were 415.8 ng/dL and 395.9 ng/dL.
“Of note, more than 90% of men enrolled in this study had at least one cardiovascular risk factor,” Dr. Shore said. “Tobacco use and obesity were common, as were diabetes and hypertension. Fourteen percent of men reported a prior history of major adverse cardiovascular event, such as a heart attack or stroke; this is lower than the 30% expected in a typical population of men with advanced prostate cancer given the study’s cardiovascular exclusion criteria.”
Efficacy
Sustained testosterone suppression to castration levels (less than 50 ng/dL) was achieved through 48 weeks in 96.7% of patients on relugolix, compared with 88.8% of men on leuprolide.
The absolute difference of 7.9% reached the statistical definitions for both noninferiority and superiority of relugolix over leuprolide (P for superiority < .001).
Mean testosterone levels on day 4 had decreased to below 50 ng/dL for relugolix and were maintained at castration levels until the end of treatment. In the leuprolide group, the mean testosterone level on day 4 was 625 ng/dL, which declined to castration levels by day 29 and remained below 50 ng/dL after the end of treatment at week 53. In contrast, testosterone levels in the relugolix arm began to recover immediately after the cessation of therapy.
Results with relugolix were significantly better than with leuprolide for the following endpoints (P < .0001 for all comparisons):
- Proportion of patients with PSA response at day 15 and confirmed at day 29 (79.4% vs. 19.8%)
- Cumulative probability of testosterone suppression to less than 50 ng/dL on day 15 (98.7% vs. 12.05%)
- Cumulative probability of profound testosterone suppression to less than 20 ng/dL on day 15 (78.38% vs. 0.98%)
- Mean follicle-stimulating hormone level at the end of week 24 (1.72 vs. 5.95 IU/L).
Safety
Treatment-related adverse events occurred in 73.6% of patients treated with relugolix and 68.8% of those who received leuprolide. Grade 3 or greater adverse events occurred in 3.4% and 2.6%, respectively. The respective incidences of fatal adverse events were 1.1% and 2.9%.
At 48 weeks, MACE had occurred in 2.9% of patients on relugolix and 6.2% on leuprolide. Among men with a history of a MACE event more than 6 months before study entry, leuprolide was associated with a nearly sixfold increased risk for a new MACE.
The investigators also found that compliance with the assigned medication was greater than 99% in each study arm, allaying concerns that men assigned to the oral therapy might be less likely to faithfully take their medicine.
Antagonists vs. agonists
Agents such as relugolix, which are, in effect, LHRH antagonists, have several advantages over LHRH agonists, according to invited discussant Elahe Mostaghel, MD, PhD, of the VA Puget Sound Health Care System and Fred Hutchinson Cancer Research Center, both in Seattle.
“Cost and access aside, antagonists have potential benefits over agonists, each of which may be more or less important, depending on context,” she said.
Antagonists have a more rapid onset of castration, lack the flare response seen with agonists such as leuprolide, and are associated with a significant decrease in risk for MACE.
“Differences in depth and consistency of androgen suppression may also be important. LHRH antagonists may be superior to LHRH agonists in this regard, although this remains to be fully proven, while rapid testosterone recovery and oral administration may also have benefits in particular contexts,” Dr. Mostaghel said.
“It is likely that the anticancer effects of a GnRH antagonist will not be inferior to those of a GnRH agonist and may be beneficial in terms of cardiovascular events that may be life-limiting,” Celestia S. Higano, MD, of the University of Washington in Seattle wrote in an editorial accompanying the HERO study in The New England Journal of Medicine.
“Close monitoring will be required because exposure to oral relugolix for longer than 48 weeks has not been studied and many oral agents are associated with adherence problems, especially if they cause adverse effects,” Dr. Higano added.
The HERO study was supported by Myovant. Dr. Shore disclosed relationships with Myovant and other companies. Dr. Mostaghel disclosed affiliations with Context Therapeutics. Dr. Hinago disclosed grants and fees from various companies, not including Myovant.
SOURCES: Shore ND et al. ASCO 2020, Abstract 5602; N Engl J Med. 2020 May 29. doi: 10.1056/NEJMoa2004325.
FROM ASCO 2020
Short-course radiotherapy and chemo may reduce treatment failures in high-risk rectal cancer
For patients with high-risk locally advanced rectal cancer, a short course of radiotherapy followed by consolidative chemotherapy and then surgery significantly reduced the rate of treatment failure, compared with standard chemoradiotherapy, results of a randomized trial show.
according to investigator Geke A.P. Hospers, MD, PhD.
The rate of pathological complete response (pCR) nearly doubled, from about 14% for the conventional approach to about 28% for short-course (25 Gy in 5 fractions) radiotherapy then CAPOX or FOLFOX4 followed by total mesorectal excision (TME), reported Dr. Hospers, a medical oncologist and professor at University Medical Center Groningen in the Netherlands.
Three-year survival was high at about 89% in both groups, she said, with no unexpected toxicity and no differences in surgery, postoperative complications, or quality of life.
Based on these results, the short-course radiotherapy followed by chemotherapy and TME “can be considered as a new standard of care,” Dr. Hospers and coauthors concluded in their report on the RAPIDO trial, which was of part of the American Society of Clinical Oncology virtual scientific program.
In agreement was Christopher L. Hallemeier, MD, who said in a virtual ASCO discussion of the RAPIDO trial that short-course radiotherapy followed by consolidative chemotherapy “is a standard option” for many patients and is, in fact, now endorsed in National Comprehensive Cancer Network (NCCN) guidelines.
“I should point out that 5 fractions of radiotherapy is COVID-19 friendly in that it reduces the number of visits to the health care facility,” said Dr. Hallemeier, of Mayo Clinic in Rochester, Minn.
Several questions remain, however, including whether clinicians should be concerned about a trend toward a higher risk of locoregional failure seen in the RAPIDO results and why there was a lack of difference in OS.
“Could it be we’re merely delaying distant metastases versus preventing them by more consistent use of systemic therapy sooner? Longer-term follow-up will be needed to determine whether that’s the case,” he said.
In RAPIDO, a total of 920 adult patients with adenocarcinoma of the rectum and high-risk features apparent on MRI were randomized to a standard chemoradiation arm or the experimental approach.
In the standard treatment arm, patients received chemoradiotherapy (28 fractions x 1.8 Gy or 25 fractions x 2 Gy combined with capecitabine) followed by surgery about 8 weeks later, then optional adjuvant chemotherapy (CAPOX for 8 courses or FOLFOX for 12 courses) in the centers where that approach was standard.
The experimental treatment consisted of short-course radiotherapy (5 fractions x 5 Gy) followed by chemotherapy (CAPOX for 6 courses or FOLFOX for 9 courses), then surgery 2-4 weeks later.
Disease-related treatment failure, the primary endpoint of the study, was significantly lower in the experimental arm, according to Dr. Hospers. The 3-year rate of disease-related treatment failure was 23.7% for the experimental treatment and 30.4% for standard chemoradiotherapy (hazard ratio, 0.75; 95% confidence interval, 0.60-0.96; P = .019).
According to Dr. Hospers, the difference in rates of treatment failure was primarily caused by a significant decrease in distant metastases, at 20% and 26.8% in the experimental and standard treatment arms, respectively, at 3 years (P = .005).
The rate of pCR was 28.4% for the experimental arm, versus 14.3% for standard treatment (P < .001), Dr. Hospers reported.
Grade 3 or greater neurologic toxicity was more common in the experimental arm, occurring in 4.3% versus 0.2% in the standard treatment arm, which Dr. Hospers said was expected because of the administration of oxaplatin. Likewise, there was a higher percentage of grade 3 or greater thromboembolic events in the experimental group (8.5% vs. 4.1%) and more grade 3 or greater diarrhea (17.6% vs. 9.3%).
Subgroup analysis showed that the experimental approach was favored over conventional chemoradiotherapy whether or not patients in the conventional arm went on to receive the optional adjuvant chemotherapy, according to Dr. Hospers.
Results of RAPIDO have the potential to change the standard of care for locally advanced rectal cancer, according to Suneel Kamath, MD, a gastrointestinal oncologist with Cleveland Clinic in Cleveland, Ohio.
The pCR rate with short-course radiation followed by chemotherapy is “excellent,” compared with what’s typically seen with standard, long-course chemoradiation, Dr. Kamath said in an interview.
“This proves that we don’t necessarily need long-course radiation for larger tumors or larger number of lymph nodes to get good down-staging,” he said.
The lower rate of distant metastatic disease with the short-course radiation and preoperative chemotherapy arm was also notable, Dr. Kamath said.
The study was sponsored by the University Medical Center Groningen. Dr. Hospers reported institutional disclosures related to Amgen, Bristol-Myers Squibb, MSD, Novartis, Roche, and Seerave Foundation. Dr. Hallemeier reported honoraria and travel expenses from Focus Medical Communications and Imedex. Dr. Kamath had no relevant disclosures.
SOURCE: Hospers GAP et al. ASCO 2020, Abstract 4006.
For patients with high-risk locally advanced rectal cancer, a short course of radiotherapy followed by consolidative chemotherapy and then surgery significantly reduced the rate of treatment failure, compared with standard chemoradiotherapy, results of a randomized trial show.
according to investigator Geke A.P. Hospers, MD, PhD.
The rate of pathological complete response (pCR) nearly doubled, from about 14% for the conventional approach to about 28% for short-course (25 Gy in 5 fractions) radiotherapy then CAPOX or FOLFOX4 followed by total mesorectal excision (TME), reported Dr. Hospers, a medical oncologist and professor at University Medical Center Groningen in the Netherlands.
Three-year survival was high at about 89% in both groups, she said, with no unexpected toxicity and no differences in surgery, postoperative complications, or quality of life.
Based on these results, the short-course radiotherapy followed by chemotherapy and TME “can be considered as a new standard of care,” Dr. Hospers and coauthors concluded in their report on the RAPIDO trial, which was of part of the American Society of Clinical Oncology virtual scientific program.
In agreement was Christopher L. Hallemeier, MD, who said in a virtual ASCO discussion of the RAPIDO trial that short-course radiotherapy followed by consolidative chemotherapy “is a standard option” for many patients and is, in fact, now endorsed in National Comprehensive Cancer Network (NCCN) guidelines.
“I should point out that 5 fractions of radiotherapy is COVID-19 friendly in that it reduces the number of visits to the health care facility,” said Dr. Hallemeier, of Mayo Clinic in Rochester, Minn.
Several questions remain, however, including whether clinicians should be concerned about a trend toward a higher risk of locoregional failure seen in the RAPIDO results and why there was a lack of difference in OS.
“Could it be we’re merely delaying distant metastases versus preventing them by more consistent use of systemic therapy sooner? Longer-term follow-up will be needed to determine whether that’s the case,” he said.
In RAPIDO, a total of 920 adult patients with adenocarcinoma of the rectum and high-risk features apparent on MRI were randomized to a standard chemoradiation arm or the experimental approach.
In the standard treatment arm, patients received chemoradiotherapy (28 fractions x 1.8 Gy or 25 fractions x 2 Gy combined with capecitabine) followed by surgery about 8 weeks later, then optional adjuvant chemotherapy (CAPOX for 8 courses or FOLFOX for 12 courses) in the centers where that approach was standard.
The experimental treatment consisted of short-course radiotherapy (5 fractions x 5 Gy) followed by chemotherapy (CAPOX for 6 courses or FOLFOX for 9 courses), then surgery 2-4 weeks later.
Disease-related treatment failure, the primary endpoint of the study, was significantly lower in the experimental arm, according to Dr. Hospers. The 3-year rate of disease-related treatment failure was 23.7% for the experimental treatment and 30.4% for standard chemoradiotherapy (hazard ratio, 0.75; 95% confidence interval, 0.60-0.96; P = .019).
According to Dr. Hospers, the difference in rates of treatment failure was primarily caused by a significant decrease in distant metastases, at 20% and 26.8% in the experimental and standard treatment arms, respectively, at 3 years (P = .005).
The rate of pCR was 28.4% for the experimental arm, versus 14.3% for standard treatment (P < .001), Dr. Hospers reported.
Grade 3 or greater neurologic toxicity was more common in the experimental arm, occurring in 4.3% versus 0.2% in the standard treatment arm, which Dr. Hospers said was expected because of the administration of oxaplatin. Likewise, there was a higher percentage of grade 3 or greater thromboembolic events in the experimental group (8.5% vs. 4.1%) and more grade 3 or greater diarrhea (17.6% vs. 9.3%).
Subgroup analysis showed that the experimental approach was favored over conventional chemoradiotherapy whether or not patients in the conventional arm went on to receive the optional adjuvant chemotherapy, according to Dr. Hospers.
Results of RAPIDO have the potential to change the standard of care for locally advanced rectal cancer, according to Suneel Kamath, MD, a gastrointestinal oncologist with Cleveland Clinic in Cleveland, Ohio.
The pCR rate with short-course radiation followed by chemotherapy is “excellent,” compared with what’s typically seen with standard, long-course chemoradiation, Dr. Kamath said in an interview.
“This proves that we don’t necessarily need long-course radiation for larger tumors or larger number of lymph nodes to get good down-staging,” he said.
The lower rate of distant metastatic disease with the short-course radiation and preoperative chemotherapy arm was also notable, Dr. Kamath said.
The study was sponsored by the University Medical Center Groningen. Dr. Hospers reported institutional disclosures related to Amgen, Bristol-Myers Squibb, MSD, Novartis, Roche, and Seerave Foundation. Dr. Hallemeier reported honoraria and travel expenses from Focus Medical Communications and Imedex. Dr. Kamath had no relevant disclosures.
SOURCE: Hospers GAP et al. ASCO 2020, Abstract 4006.
For patients with high-risk locally advanced rectal cancer, a short course of radiotherapy followed by consolidative chemotherapy and then surgery significantly reduced the rate of treatment failure, compared with standard chemoradiotherapy, results of a randomized trial show.
according to investigator Geke A.P. Hospers, MD, PhD.
The rate of pathological complete response (pCR) nearly doubled, from about 14% for the conventional approach to about 28% for short-course (25 Gy in 5 fractions) radiotherapy then CAPOX or FOLFOX4 followed by total mesorectal excision (TME), reported Dr. Hospers, a medical oncologist and professor at University Medical Center Groningen in the Netherlands.
Three-year survival was high at about 89% in both groups, she said, with no unexpected toxicity and no differences in surgery, postoperative complications, or quality of life.
Based on these results, the short-course radiotherapy followed by chemotherapy and TME “can be considered as a new standard of care,” Dr. Hospers and coauthors concluded in their report on the RAPIDO trial, which was of part of the American Society of Clinical Oncology virtual scientific program.
In agreement was Christopher L. Hallemeier, MD, who said in a virtual ASCO discussion of the RAPIDO trial that short-course radiotherapy followed by consolidative chemotherapy “is a standard option” for many patients and is, in fact, now endorsed in National Comprehensive Cancer Network (NCCN) guidelines.
“I should point out that 5 fractions of radiotherapy is COVID-19 friendly in that it reduces the number of visits to the health care facility,” said Dr. Hallemeier, of Mayo Clinic in Rochester, Minn.
Several questions remain, however, including whether clinicians should be concerned about a trend toward a higher risk of locoregional failure seen in the RAPIDO results and why there was a lack of difference in OS.
“Could it be we’re merely delaying distant metastases versus preventing them by more consistent use of systemic therapy sooner? Longer-term follow-up will be needed to determine whether that’s the case,” he said.
In RAPIDO, a total of 920 adult patients with adenocarcinoma of the rectum and high-risk features apparent on MRI were randomized to a standard chemoradiation arm or the experimental approach.
In the standard treatment arm, patients received chemoradiotherapy (28 fractions x 1.8 Gy or 25 fractions x 2 Gy combined with capecitabine) followed by surgery about 8 weeks later, then optional adjuvant chemotherapy (CAPOX for 8 courses or FOLFOX for 12 courses) in the centers where that approach was standard.
The experimental treatment consisted of short-course radiotherapy (5 fractions x 5 Gy) followed by chemotherapy (CAPOX for 6 courses or FOLFOX for 9 courses), then surgery 2-4 weeks later.
Disease-related treatment failure, the primary endpoint of the study, was significantly lower in the experimental arm, according to Dr. Hospers. The 3-year rate of disease-related treatment failure was 23.7% for the experimental treatment and 30.4% for standard chemoradiotherapy (hazard ratio, 0.75; 95% confidence interval, 0.60-0.96; P = .019).
According to Dr. Hospers, the difference in rates of treatment failure was primarily caused by a significant decrease in distant metastases, at 20% and 26.8% in the experimental and standard treatment arms, respectively, at 3 years (P = .005).
The rate of pCR was 28.4% for the experimental arm, versus 14.3% for standard treatment (P < .001), Dr. Hospers reported.
Grade 3 or greater neurologic toxicity was more common in the experimental arm, occurring in 4.3% versus 0.2% in the standard treatment arm, which Dr. Hospers said was expected because of the administration of oxaplatin. Likewise, there was a higher percentage of grade 3 or greater thromboembolic events in the experimental group (8.5% vs. 4.1%) and more grade 3 or greater diarrhea (17.6% vs. 9.3%).
Subgroup analysis showed that the experimental approach was favored over conventional chemoradiotherapy whether or not patients in the conventional arm went on to receive the optional adjuvant chemotherapy, according to Dr. Hospers.
Results of RAPIDO have the potential to change the standard of care for locally advanced rectal cancer, according to Suneel Kamath, MD, a gastrointestinal oncologist with Cleveland Clinic in Cleveland, Ohio.
The pCR rate with short-course radiation followed by chemotherapy is “excellent,” compared with what’s typically seen with standard, long-course chemoradiation, Dr. Kamath said in an interview.
“This proves that we don’t necessarily need long-course radiation for larger tumors or larger number of lymph nodes to get good down-staging,” he said.
The lower rate of distant metastatic disease with the short-course radiation and preoperative chemotherapy arm was also notable, Dr. Kamath said.
The study was sponsored by the University Medical Center Groningen. Dr. Hospers reported institutional disclosures related to Amgen, Bristol-Myers Squibb, MSD, Novartis, Roche, and Seerave Foundation. Dr. Hallemeier reported honoraria and travel expenses from Focus Medical Communications and Imedex. Dr. Kamath had no relevant disclosures.
SOURCE: Hospers GAP et al. ASCO 2020, Abstract 4006.
FROM ASCO 2020
Tucatinib improves PFS, OS in HER2+ breast cancer with brain metastases
In HER2-positive breast cancer patients with brain metastases treated with trastuzumab and capecitabine, add-on tucatinib increased median overall survival from 12 months to 18.1 months in a phase 2 trial.
The results were presented as part of the American Society of Clinical Oncology virtual scientific program and published simultaneously in the Journal of Clinical Oncology.
At 1 year, 70% of the 198 patients who had been randomized to tucatinib were alive versus 47% of the 93 patients randomized to placebo. Tucatinib reduced the risk of death by 42% (P = .005).
“This is the first double-blind, randomized trial of systemic therapy to our knowledge [that demonstrated] clinically meaningful gains in [overall survival] among patients with [brain metastases], including those with active metastases,” Nancy Lin, MD, associate chief of the division of breast oncology at Dana-Farber Cancer Institute in Boston and colleagues wrote in the Journal of Clinical Oncology.
The findings come from a substudy of the HER2CLIMB trial, which had similar outcomes but didn’t separate women with brain metastases from others. The study won tucatinib’s maker, Seattle Genetics, Food and Drug Administration approval for tucatinib in combination with trastuzumab and capecitabine for patients with unresectable or metastatic HER2-postive disease after failure of at least one treatment for advanced disease. In the United States, tucatinib costs over $18,000 a month, according to GoodRX and other sources.
The newly approved indication for tucatinib includes patients with brain metastases, but Dr. Lin and colleagues drove the point home by analyzing HER2CLIMB data solely in the 291 subjects who had baseline CNS lesions, which occur in up to half of women with advanced HER2-positive breast cancer.
Amy Tiersten, MD, a professor at Mount Sinai Hospital in New York, was not involved in the study but is convinced of the clinical benefit of tucatinib. Tucatinib “will be the standard of care for all patients with brain metastases ... regardless of” previous treatments, she said.
“It’s a total game changer. The addition of tucatinib made a large difference, including a hefty impact on overall survival. It will be interesting to see if this drug will be useful in earlier stages to help prevent brain metastases,” Dr. Tiersten said.
Among the large benefits she alluded to, the median CNS progression-free survival (PFS) – free of lesion progression or death – was 9.9 months with tucatinib versus 4.2 months with placebo (P < .00001).
At 1 year, 40% of tucatinib patients, but no patients in the placebo arm, were alive and free of CNS progression. Tucatinib reduced the risk of intracranial progression or death by 68%.
Active vs. stable brain metastasis
Among the 117 patients who entered the trial with stable, treated brain metastases – most by radiation, the rest by surgery – the median CNS PFS was 13.9 months with tucatinib versus 5.6 months with placebo (P = .002). In this group, the median overall survival was 15.7 months in the tucatinib arm and 13.6 month in the placebo arm (P = .70).
“Overall survival [in stable patients] numerically favored tucatinib to a small extent, but this did not reach statistical significance, albeit in a relatively small number of patients,” Dr. Lin said in her presentation.
Between-arm differences were significant in the 174 patients who entered the trial with active brain metastases, which refers to those that were either known but untreated, newly discovered on baseline MRI, or progressed after treatment. At 1 year, 35% of these patients in the tucatinib arm were still alive and free of CNS progression; however, there were no such patients in the placebo arm.
The median CNS PFS among patients with active brain metastases at study entrance was 9.5 months with tucatinib versus 4.1 months in the placebo arm (P < .0001). The median overall survival was 20.7 months and 11.6 months, respectively (P = .004).
Intracranial response was confirmed by MRI in 47% of tucatinib-treated patients with active brain metastasis at baseline versus 20% of patients on placebo (P = .03).
Re-treatment after progression
Thirty subjects – 21 on tucatinib and 9 on placebo – returned to their study arm after radiation for brain lesion progression.
The risk of second progression or death was reduced 67% when patients restarted tucatinib instead of placebo.
The median time from first CNS progression to a second progression or death was 7.6 months with tucatinib versus 3.1 months with placebo (P = .02).
“The data suggest a potential benefit for continuation of tucatinib beyond first isolated CNS progression,” Dr. Lin said.
As for why tucatinib helps, she and her colleagues speculated that, because tyrosine kinase inhibitors are small molecules, they can cross the blood brain barrier and effectively treat CNS lesions, while larger, antibody-based anti-HER2 agents, such as trastuzumab and pertuzumab, cannot.
Study entry required prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine, as well as an Eastern Cooperative Oncology Group performance score of 0 or 1. More than 99% of the subjects in the analysis were women, and the median age was 52 years.
The treatment groups were well balanced. A bit over half of the subjects in both arms were in North America, and 57% were estrogen and/or progesterone receptor positive. Adverse events were reported previously.
This research was funded by tucatinib’s maker, Seattle Genetics. Dr. Lin and colleagues disclosed financial relationships with Seattle Genetics, including employment. Dr. Tiersten reported no relevant conflicts of interest.
SOURCE: Lin NU et al. ASCO 2020, Abstract 1005; J Clin Oncol. 2020 May 29. doi: 10.1200/JCO.20.00775
In HER2-positive breast cancer patients with brain metastases treated with trastuzumab and capecitabine, add-on tucatinib increased median overall survival from 12 months to 18.1 months in a phase 2 trial.
The results were presented as part of the American Society of Clinical Oncology virtual scientific program and published simultaneously in the Journal of Clinical Oncology.
At 1 year, 70% of the 198 patients who had been randomized to tucatinib were alive versus 47% of the 93 patients randomized to placebo. Tucatinib reduced the risk of death by 42% (P = .005).
“This is the first double-blind, randomized trial of systemic therapy to our knowledge [that demonstrated] clinically meaningful gains in [overall survival] among patients with [brain metastases], including those with active metastases,” Nancy Lin, MD, associate chief of the division of breast oncology at Dana-Farber Cancer Institute in Boston and colleagues wrote in the Journal of Clinical Oncology.
The findings come from a substudy of the HER2CLIMB trial, which had similar outcomes but didn’t separate women with brain metastases from others. The study won tucatinib’s maker, Seattle Genetics, Food and Drug Administration approval for tucatinib in combination with trastuzumab and capecitabine for patients with unresectable or metastatic HER2-postive disease after failure of at least one treatment for advanced disease. In the United States, tucatinib costs over $18,000 a month, according to GoodRX and other sources.
The newly approved indication for tucatinib includes patients with brain metastases, but Dr. Lin and colleagues drove the point home by analyzing HER2CLIMB data solely in the 291 subjects who had baseline CNS lesions, which occur in up to half of women with advanced HER2-positive breast cancer.
Amy Tiersten, MD, a professor at Mount Sinai Hospital in New York, was not involved in the study but is convinced of the clinical benefit of tucatinib. Tucatinib “will be the standard of care for all patients with brain metastases ... regardless of” previous treatments, she said.
“It’s a total game changer. The addition of tucatinib made a large difference, including a hefty impact on overall survival. It will be interesting to see if this drug will be useful in earlier stages to help prevent brain metastases,” Dr. Tiersten said.
Among the large benefits she alluded to, the median CNS progression-free survival (PFS) – free of lesion progression or death – was 9.9 months with tucatinib versus 4.2 months with placebo (P < .00001).
At 1 year, 40% of tucatinib patients, but no patients in the placebo arm, were alive and free of CNS progression. Tucatinib reduced the risk of intracranial progression or death by 68%.
Active vs. stable brain metastasis
Among the 117 patients who entered the trial with stable, treated brain metastases – most by radiation, the rest by surgery – the median CNS PFS was 13.9 months with tucatinib versus 5.6 months with placebo (P = .002). In this group, the median overall survival was 15.7 months in the tucatinib arm and 13.6 month in the placebo arm (P = .70).
“Overall survival [in stable patients] numerically favored tucatinib to a small extent, but this did not reach statistical significance, albeit in a relatively small number of patients,” Dr. Lin said in her presentation.
Between-arm differences were significant in the 174 patients who entered the trial with active brain metastases, which refers to those that were either known but untreated, newly discovered on baseline MRI, or progressed after treatment. At 1 year, 35% of these patients in the tucatinib arm were still alive and free of CNS progression; however, there were no such patients in the placebo arm.
The median CNS PFS among patients with active brain metastases at study entrance was 9.5 months with tucatinib versus 4.1 months in the placebo arm (P < .0001). The median overall survival was 20.7 months and 11.6 months, respectively (P = .004).
Intracranial response was confirmed by MRI in 47% of tucatinib-treated patients with active brain metastasis at baseline versus 20% of patients on placebo (P = .03).
Re-treatment after progression
Thirty subjects – 21 on tucatinib and 9 on placebo – returned to their study arm after radiation for brain lesion progression.
The risk of second progression or death was reduced 67% when patients restarted tucatinib instead of placebo.
The median time from first CNS progression to a second progression or death was 7.6 months with tucatinib versus 3.1 months with placebo (P = .02).
“The data suggest a potential benefit for continuation of tucatinib beyond first isolated CNS progression,” Dr. Lin said.
As for why tucatinib helps, she and her colleagues speculated that, because tyrosine kinase inhibitors are small molecules, they can cross the blood brain barrier and effectively treat CNS lesions, while larger, antibody-based anti-HER2 agents, such as trastuzumab and pertuzumab, cannot.
Study entry required prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine, as well as an Eastern Cooperative Oncology Group performance score of 0 or 1. More than 99% of the subjects in the analysis were women, and the median age was 52 years.
The treatment groups were well balanced. A bit over half of the subjects in both arms were in North America, and 57% were estrogen and/or progesterone receptor positive. Adverse events were reported previously.
This research was funded by tucatinib’s maker, Seattle Genetics. Dr. Lin and colleagues disclosed financial relationships with Seattle Genetics, including employment. Dr. Tiersten reported no relevant conflicts of interest.
SOURCE: Lin NU et al. ASCO 2020, Abstract 1005; J Clin Oncol. 2020 May 29. doi: 10.1200/JCO.20.00775
In HER2-positive breast cancer patients with brain metastases treated with trastuzumab and capecitabine, add-on tucatinib increased median overall survival from 12 months to 18.1 months in a phase 2 trial.
The results were presented as part of the American Society of Clinical Oncology virtual scientific program and published simultaneously in the Journal of Clinical Oncology.
At 1 year, 70% of the 198 patients who had been randomized to tucatinib were alive versus 47% of the 93 patients randomized to placebo. Tucatinib reduced the risk of death by 42% (P = .005).
“This is the first double-blind, randomized trial of systemic therapy to our knowledge [that demonstrated] clinically meaningful gains in [overall survival] among patients with [brain metastases], including those with active metastases,” Nancy Lin, MD, associate chief of the division of breast oncology at Dana-Farber Cancer Institute in Boston and colleagues wrote in the Journal of Clinical Oncology.
The findings come from a substudy of the HER2CLIMB trial, which had similar outcomes but didn’t separate women with brain metastases from others. The study won tucatinib’s maker, Seattle Genetics, Food and Drug Administration approval for tucatinib in combination with trastuzumab and capecitabine for patients with unresectable or metastatic HER2-postive disease after failure of at least one treatment for advanced disease. In the United States, tucatinib costs over $18,000 a month, according to GoodRX and other sources.
The newly approved indication for tucatinib includes patients with brain metastases, but Dr. Lin and colleagues drove the point home by analyzing HER2CLIMB data solely in the 291 subjects who had baseline CNS lesions, which occur in up to half of women with advanced HER2-positive breast cancer.
Amy Tiersten, MD, a professor at Mount Sinai Hospital in New York, was not involved in the study but is convinced of the clinical benefit of tucatinib. Tucatinib “will be the standard of care for all patients with brain metastases ... regardless of” previous treatments, she said.
“It’s a total game changer. The addition of tucatinib made a large difference, including a hefty impact on overall survival. It will be interesting to see if this drug will be useful in earlier stages to help prevent brain metastases,” Dr. Tiersten said.
Among the large benefits she alluded to, the median CNS progression-free survival (PFS) – free of lesion progression or death – was 9.9 months with tucatinib versus 4.2 months with placebo (P < .00001).
At 1 year, 40% of tucatinib patients, but no patients in the placebo arm, were alive and free of CNS progression. Tucatinib reduced the risk of intracranial progression or death by 68%.
Active vs. stable brain metastasis
Among the 117 patients who entered the trial with stable, treated brain metastases – most by radiation, the rest by surgery – the median CNS PFS was 13.9 months with tucatinib versus 5.6 months with placebo (P = .002). In this group, the median overall survival was 15.7 months in the tucatinib arm and 13.6 month in the placebo arm (P = .70).
“Overall survival [in stable patients] numerically favored tucatinib to a small extent, but this did not reach statistical significance, albeit in a relatively small number of patients,” Dr. Lin said in her presentation.
Between-arm differences were significant in the 174 patients who entered the trial with active brain metastases, which refers to those that were either known but untreated, newly discovered on baseline MRI, or progressed after treatment. At 1 year, 35% of these patients in the tucatinib arm were still alive and free of CNS progression; however, there were no such patients in the placebo arm.
The median CNS PFS among patients with active brain metastases at study entrance was 9.5 months with tucatinib versus 4.1 months in the placebo arm (P < .0001). The median overall survival was 20.7 months and 11.6 months, respectively (P = .004).
Intracranial response was confirmed by MRI in 47% of tucatinib-treated patients with active brain metastasis at baseline versus 20% of patients on placebo (P = .03).
Re-treatment after progression
Thirty subjects – 21 on tucatinib and 9 on placebo – returned to their study arm after radiation for brain lesion progression.
The risk of second progression or death was reduced 67% when patients restarted tucatinib instead of placebo.
The median time from first CNS progression to a second progression or death was 7.6 months with tucatinib versus 3.1 months with placebo (P = .02).
“The data suggest a potential benefit for continuation of tucatinib beyond first isolated CNS progression,” Dr. Lin said.
As for why tucatinib helps, she and her colleagues speculated that, because tyrosine kinase inhibitors are small molecules, they can cross the blood brain barrier and effectively treat CNS lesions, while larger, antibody-based anti-HER2 agents, such as trastuzumab and pertuzumab, cannot.
Study entry required prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine, as well as an Eastern Cooperative Oncology Group performance score of 0 or 1. More than 99% of the subjects in the analysis were women, and the median age was 52 years.
The treatment groups were well balanced. A bit over half of the subjects in both arms were in North America, and 57% were estrogen and/or progesterone receptor positive. Adverse events were reported previously.
This research was funded by tucatinib’s maker, Seattle Genetics. Dr. Lin and colleagues disclosed financial relationships with Seattle Genetics, including employment. Dr. Tiersten reported no relevant conflicts of interest.
SOURCE: Lin NU et al. ASCO 2020, Abstract 1005; J Clin Oncol. 2020 May 29. doi: 10.1200/JCO.20.00775
FROM ASCO 2020
TRAIN-2: Anthracyclines added toxicity, with no increased efficacy, in HER2+ breast cancer
Anthracyclines add toxicity with no evidence of improved survival in patients with HER2-positive breast cancer receiving a neoadjuvant chemotherapy regimen plus dual HER2 blockade, results of a phase 3 trial have suggested.
Event-free survival (EFS) estimates at 3 years were 93% for patients receiving anthracycline-containing chemotherapy plus trastuzumab/pertuzumab and 94% for those receiving an anthracycline-free regimen, according to long-term follow-up results of TRAIN-2, a randomized, phase 3 trial.
There was also “no evidence” that higher-risk patients would benefit from anthracyclines, said investigator Anna Van der Voort of the Netherlands Cancer Institute in Amsterdam.
“Today, anthracyclines are often used, especially in patients with higher risk of recurrence,” said Ms. Van der Voort in her presentation, which was part of the American Society of Clinical Oncology (ASCO) virtual scientific program.
“Importantly, anthracyclines increased the risk of febrile neutropenia, cardiac toxicity, and chemotherapy-associated leukemia, and therefore, a neoadjuvant anthracycline-free regimen with dual HER2 blockade should be considered in all stage II and III HER2-positive breast cancer patients,” she suggested.
With these new results, there are now “great safety data and very promising efficacy data” from two comparative studies favoring nonanthracycline regimens plus HER2 blockade over an anthracycline approach, even in patients with disease thought to be at high risk of recurrence, said Sara A. Hurvitz, MD, associate professor of medicine at the University of California Los Angeles Jonsson Comprehensive Cancer Center.
The other comparative study, BCIRG-006, demonstrated that docetaxel and carboplatin plus trastuzumab (TCH) had similar efficacy, fewer acute toxicities, and less cardiotoxicity and leukemia than did doxorubicin/cyclophosphamide followed by docetaxel (AC-T).
In a follow-up analysis focused on patients with four or more positive lymph nodes, disease-free survival was similar for the nonanthracycline and anthracycline regimens, Dr. Hurvitz noted.
“I would challenge us to think carefully about the standard use of anthracyclines when we have so many targeted therapies available for our patients with HER2-positive disease now,” Dr. Hurvitz said in her commentary on TRAIN-2 that was also part of the virtual ASCO proceedings.
The TRAIN-2 trial included 438 patients in the Netherlands with previously untreated stage II to III HER2-positive breast cancer. Patients randomized to the anthracycline-containing arm received 5-fluorouracil, epirubicin, and cyclophosphamide in three 3-week cycles followed by paclitaxel and carboplatin in six 3-week cycles.
Patients in the anthracycline-free arm received paclitaxel and carboplatin for nine 3-week cycles. Both groups also received trastuzumab and pertuzumab concurrent with chemotherapy.
The pathological complete response (pCR) rate was high with and without anthracyclines, Ms. Van der Voort said, referring to primary results of TRAIN-2 previously published in Lancet Oncology.
In that report, pCR was seen in 67% of patients in the anthracycline group, and 68% in the nonanthracycline group (P = .95), a finding that was consistent regardless of tumor size, nodal status, or hormone receptor status, said Ms. Van der Voort. She added that significantly more febrile neutropenia and hypokalemia were seen in the anthracycline group.
At virtual ASCO, Ms. Van der Voort presented results of the EFS analysis. At the time of analysis, there were 21 events among 219 patients in the nonanthracycline group (10%) and 23 events among 219 patients in the anthracycline group (11%). The corresponding 3-year EFS estimates were 93.5% and 92.7%, with a hazard ratio that favored the nonanthracycline group, though the difference between arms was not statistically significant (hazard ratio, 0.90; 95% confidence interval, 0.50-1.63).
“The results were independent of hormone receptor status, age, tumor size, nodal status, and grade, so we found no evidence that high-risk patients require anthracyclines,” said Ms. Van der Voort. Of note, results divided by nodal status suggested similar or better outcomes in the absence of anthracyclines, even in the highest-risk group, she added.
Estimated 3-year overall survival rates were likewise similar between groups, at 98.2% and 97.7% in the nonanthracycline and anthracycline arms, respectively.
Declines in left ventricular ejection fraction were more frequent in the anthracycline group (36% vs. 22% for the nonanthracycline group; P = .0016), and about one-third of patients did not recover that decline. New malignancies were found in 5% of the anthracycline group and 2% of the nonanthracycline group.
The TRAIN-2 study was sponsored by the Netherlands Cancer Institute and Roche. Ms. Van der Voort said she had no relationships to disclose. Dr. Hurwitz reported institutional research funding from multiple pharmaceutical companies including Genentech/Roche.
SOURCE: Van der Voort A et al. ASCO 2020, Abstract 501.
Anthracyclines add toxicity with no evidence of improved survival in patients with HER2-positive breast cancer receiving a neoadjuvant chemotherapy regimen plus dual HER2 blockade, results of a phase 3 trial have suggested.
Event-free survival (EFS) estimates at 3 years were 93% for patients receiving anthracycline-containing chemotherapy plus trastuzumab/pertuzumab and 94% for those receiving an anthracycline-free regimen, according to long-term follow-up results of TRAIN-2, a randomized, phase 3 trial.
There was also “no evidence” that higher-risk patients would benefit from anthracyclines, said investigator Anna Van der Voort of the Netherlands Cancer Institute in Amsterdam.
“Today, anthracyclines are often used, especially in patients with higher risk of recurrence,” said Ms. Van der Voort in her presentation, which was part of the American Society of Clinical Oncology (ASCO) virtual scientific program.
“Importantly, anthracyclines increased the risk of febrile neutropenia, cardiac toxicity, and chemotherapy-associated leukemia, and therefore, a neoadjuvant anthracycline-free regimen with dual HER2 blockade should be considered in all stage II and III HER2-positive breast cancer patients,” she suggested.
With these new results, there are now “great safety data and very promising efficacy data” from two comparative studies favoring nonanthracycline regimens plus HER2 blockade over an anthracycline approach, even in patients with disease thought to be at high risk of recurrence, said Sara A. Hurvitz, MD, associate professor of medicine at the University of California Los Angeles Jonsson Comprehensive Cancer Center.
The other comparative study, BCIRG-006, demonstrated that docetaxel and carboplatin plus trastuzumab (TCH) had similar efficacy, fewer acute toxicities, and less cardiotoxicity and leukemia than did doxorubicin/cyclophosphamide followed by docetaxel (AC-T).
In a follow-up analysis focused on patients with four or more positive lymph nodes, disease-free survival was similar for the nonanthracycline and anthracycline regimens, Dr. Hurvitz noted.
“I would challenge us to think carefully about the standard use of anthracyclines when we have so many targeted therapies available for our patients with HER2-positive disease now,” Dr. Hurvitz said in her commentary on TRAIN-2 that was also part of the virtual ASCO proceedings.
The TRAIN-2 trial included 438 patients in the Netherlands with previously untreated stage II to III HER2-positive breast cancer. Patients randomized to the anthracycline-containing arm received 5-fluorouracil, epirubicin, and cyclophosphamide in three 3-week cycles followed by paclitaxel and carboplatin in six 3-week cycles.
Patients in the anthracycline-free arm received paclitaxel and carboplatin for nine 3-week cycles. Both groups also received trastuzumab and pertuzumab concurrent with chemotherapy.
The pathological complete response (pCR) rate was high with and without anthracyclines, Ms. Van der Voort said, referring to primary results of TRAIN-2 previously published in Lancet Oncology.
In that report, pCR was seen in 67% of patients in the anthracycline group, and 68% in the nonanthracycline group (P = .95), a finding that was consistent regardless of tumor size, nodal status, or hormone receptor status, said Ms. Van der Voort. She added that significantly more febrile neutropenia and hypokalemia were seen in the anthracycline group.
At virtual ASCO, Ms. Van der Voort presented results of the EFS analysis. At the time of analysis, there were 21 events among 219 patients in the nonanthracycline group (10%) and 23 events among 219 patients in the anthracycline group (11%). The corresponding 3-year EFS estimates were 93.5% and 92.7%, with a hazard ratio that favored the nonanthracycline group, though the difference between arms was not statistically significant (hazard ratio, 0.90; 95% confidence interval, 0.50-1.63).
“The results were independent of hormone receptor status, age, tumor size, nodal status, and grade, so we found no evidence that high-risk patients require anthracyclines,” said Ms. Van der Voort. Of note, results divided by nodal status suggested similar or better outcomes in the absence of anthracyclines, even in the highest-risk group, she added.
Estimated 3-year overall survival rates were likewise similar between groups, at 98.2% and 97.7% in the nonanthracycline and anthracycline arms, respectively.
Declines in left ventricular ejection fraction were more frequent in the anthracycline group (36% vs. 22% for the nonanthracycline group; P = .0016), and about one-third of patients did not recover that decline. New malignancies were found in 5% of the anthracycline group and 2% of the nonanthracycline group.
The TRAIN-2 study was sponsored by the Netherlands Cancer Institute and Roche. Ms. Van der Voort said she had no relationships to disclose. Dr. Hurwitz reported institutional research funding from multiple pharmaceutical companies including Genentech/Roche.
SOURCE: Van der Voort A et al. ASCO 2020, Abstract 501.
Anthracyclines add toxicity with no evidence of improved survival in patients with HER2-positive breast cancer receiving a neoadjuvant chemotherapy regimen plus dual HER2 blockade, results of a phase 3 trial have suggested.
Event-free survival (EFS) estimates at 3 years were 93% for patients receiving anthracycline-containing chemotherapy plus trastuzumab/pertuzumab and 94% for those receiving an anthracycline-free regimen, according to long-term follow-up results of TRAIN-2, a randomized, phase 3 trial.
There was also “no evidence” that higher-risk patients would benefit from anthracyclines, said investigator Anna Van der Voort of the Netherlands Cancer Institute in Amsterdam.
“Today, anthracyclines are often used, especially in patients with higher risk of recurrence,” said Ms. Van der Voort in her presentation, which was part of the American Society of Clinical Oncology (ASCO) virtual scientific program.
“Importantly, anthracyclines increased the risk of febrile neutropenia, cardiac toxicity, and chemotherapy-associated leukemia, and therefore, a neoadjuvant anthracycline-free regimen with dual HER2 blockade should be considered in all stage II and III HER2-positive breast cancer patients,” she suggested.
With these new results, there are now “great safety data and very promising efficacy data” from two comparative studies favoring nonanthracycline regimens plus HER2 blockade over an anthracycline approach, even in patients with disease thought to be at high risk of recurrence, said Sara A. Hurvitz, MD, associate professor of medicine at the University of California Los Angeles Jonsson Comprehensive Cancer Center.
The other comparative study, BCIRG-006, demonstrated that docetaxel and carboplatin plus trastuzumab (TCH) had similar efficacy, fewer acute toxicities, and less cardiotoxicity and leukemia than did doxorubicin/cyclophosphamide followed by docetaxel (AC-T).
In a follow-up analysis focused on patients with four or more positive lymph nodes, disease-free survival was similar for the nonanthracycline and anthracycline regimens, Dr. Hurvitz noted.
“I would challenge us to think carefully about the standard use of anthracyclines when we have so many targeted therapies available for our patients with HER2-positive disease now,” Dr. Hurvitz said in her commentary on TRAIN-2 that was also part of the virtual ASCO proceedings.
The TRAIN-2 trial included 438 patients in the Netherlands with previously untreated stage II to III HER2-positive breast cancer. Patients randomized to the anthracycline-containing arm received 5-fluorouracil, epirubicin, and cyclophosphamide in three 3-week cycles followed by paclitaxel and carboplatin in six 3-week cycles.
Patients in the anthracycline-free arm received paclitaxel and carboplatin for nine 3-week cycles. Both groups also received trastuzumab and pertuzumab concurrent with chemotherapy.
The pathological complete response (pCR) rate was high with and without anthracyclines, Ms. Van der Voort said, referring to primary results of TRAIN-2 previously published in Lancet Oncology.
In that report, pCR was seen in 67% of patients in the anthracycline group, and 68% in the nonanthracycline group (P = .95), a finding that was consistent regardless of tumor size, nodal status, or hormone receptor status, said Ms. Van der Voort. She added that significantly more febrile neutropenia and hypokalemia were seen in the anthracycline group.
At virtual ASCO, Ms. Van der Voort presented results of the EFS analysis. At the time of analysis, there were 21 events among 219 patients in the nonanthracycline group (10%) and 23 events among 219 patients in the anthracycline group (11%). The corresponding 3-year EFS estimates were 93.5% and 92.7%, with a hazard ratio that favored the nonanthracycline group, though the difference between arms was not statistically significant (hazard ratio, 0.90; 95% confidence interval, 0.50-1.63).
“The results were independent of hormone receptor status, age, tumor size, nodal status, and grade, so we found no evidence that high-risk patients require anthracyclines,” said Ms. Van der Voort. Of note, results divided by nodal status suggested similar or better outcomes in the absence of anthracyclines, even in the highest-risk group, she added.
Estimated 3-year overall survival rates were likewise similar between groups, at 98.2% and 97.7% in the nonanthracycline and anthracycline arms, respectively.
Declines in left ventricular ejection fraction were more frequent in the anthracycline group (36% vs. 22% for the nonanthracycline group; P = .0016), and about one-third of patients did not recover that decline. New malignancies were found in 5% of the anthracycline group and 2% of the nonanthracycline group.
The TRAIN-2 study was sponsored by the Netherlands Cancer Institute and Roche. Ms. Van der Voort said she had no relationships to disclose. Dr. Hurwitz reported institutional research funding from multiple pharmaceutical companies including Genentech/Roche.
SOURCE: Van der Voort A et al. ASCO 2020, Abstract 501.
FROM ASCO 2020
Capecitabine maintenance improved DFS, not OS, in TNBC patients
according to results of a phase 3 trial.
Patients who received metronomic capecitabine maintenance had significantly higher rates of 5-year DFS and distant DFS, but not OS, when compared with patients who did not receive capecitabine, reported Xi Wang, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.
“TNBC has the worst outcomes among all subtypes of breast cancer,” Dr. Wang said. “Effective strategies to reduce risk of relapse are a critical clinical need.”
He went on to describe capecitabine as a “potential ideal drug for metronomic administration,” particularly among patients with high risk of distant metastasis.
With that in mind, Dr. Wang and colleagues tested metronomic capecitabine maintenance in the phase 3 SYSUCC-001 trial. The trial included 434 patients with invasive ductal carcinoma. They had undergone standard therapy, which included surgery, neoadjuvant/adjuvant chemotherapy, and radiation therapy.
Patients were randomized to receive capecitabine at 650 mg/m2 twice daily for 1 year (n = 221) or undergo observation (n = 213). The primary endpoint was DFS, while secondary endpoints included safety, distant DFS, and OS.
According to Dr. Wang, the two patient groups were “well balanced,” with similar baseline characteristics. Most patients underwent adjuvant chemotherapy (93%), had histological grade 3 tumors (71%-74%), had a Ki-67 index of at least 30% (73%-80%), had negative lymph node status (61%-62%), had a tumor size of 2.1-5 cm (55%-58%), and/or pathologic stage II disease (54%-55%).
Survival and safety
At a median follow-up of 56.5 months, the median 5-year DFS rate was 83% in the capecitabine group, compared with 73% in the observation group (P = .027). Similarly, capecitabine use correlated with a significantly better rate of distant DFS (85% vs. 76%; P = .016).
Although the capecitabine group demonstrated a slight trend toward improved OS at 5 years, this finding was not statistically significant (86% vs. 81%; P = .203).
Capecitabine was generally well tolerated, with 91% of patients completing 1 year of therapy, and 75% completing therapy at the full dose.
Almost half of patients in the capecitabine group experienced hand-foot syndrome (45%), and one in four developed leukopenia (24%). Less common adverse events included hyperbilirubinemia (13%), gastrointestinal pain (7%), and elevated serum transaminases (5%). No unexpected serious adverse events occurred.
Effects on practice
Amy Tiersten, MD, of the Icahn School of Medicine at Mount Sinai in New York, suggested these findings may lead to broader use of capecitabine among patients with TNBC.
“[This is a] very exciting study showing an impressive disease-free survival benefit in the adjuvant setting for capecitabine in patients with early stage TNBC,” Dr. Tiersten said. “Presently, we only have positive data for capecitabine in patients with residual disease after neoadjuvant therapy, but this current study now suggests that this benefit could extend to all comers.”
Dr. Tiersten advised that the medical community stay tuned, since longer-term data may provide a clearer picture of survival benefit.
“It will be interesting to see if there is an impact on overall survival with further follow-up,” she said.
According to invited discussant Naamit Kurshan Gerber, MD, of New York University, the results support previous findings from the CREATE-X trial, along with meta-analyses that have shown a “preferential benefit” of capecitabine when used to treat TNBC, compared with estrogen receptor–positive disease.
Still, Dr. Gerber noted that, for most patients, the findings from the SYSUCC-001 trial are unlikely to influence clinical decision-making since most patients with TNBC receive neoadjuvant chemotherapy followed by treatment based on pathologic response. However, she also suggested that, after peer review, the findings could influence treatment for a select few.
“For the small population of patients who receive adjuvant chemotherapy for higher-stage TNBC and who would have met eligibility criteria, this approach may be considered,” Dr. Gerber said.
The study was funded by the Sun Yat-sen University Clinical Research 5010 Program. The investigators disclosed no conflicts of interest. Dr. Gerber reported a relationship with OncLive. Dr. Tiersten reported no relevant disclosures.
SOURCE: Wang X et al. ASCO 2020, Abstract 507.
according to results of a phase 3 trial.
Patients who received metronomic capecitabine maintenance had significantly higher rates of 5-year DFS and distant DFS, but not OS, when compared with patients who did not receive capecitabine, reported Xi Wang, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.
“TNBC has the worst outcomes among all subtypes of breast cancer,” Dr. Wang said. “Effective strategies to reduce risk of relapse are a critical clinical need.”
He went on to describe capecitabine as a “potential ideal drug for metronomic administration,” particularly among patients with high risk of distant metastasis.
With that in mind, Dr. Wang and colleagues tested metronomic capecitabine maintenance in the phase 3 SYSUCC-001 trial. The trial included 434 patients with invasive ductal carcinoma. They had undergone standard therapy, which included surgery, neoadjuvant/adjuvant chemotherapy, and radiation therapy.
Patients were randomized to receive capecitabine at 650 mg/m2 twice daily for 1 year (n = 221) or undergo observation (n = 213). The primary endpoint was DFS, while secondary endpoints included safety, distant DFS, and OS.
According to Dr. Wang, the two patient groups were “well balanced,” with similar baseline characteristics. Most patients underwent adjuvant chemotherapy (93%), had histological grade 3 tumors (71%-74%), had a Ki-67 index of at least 30% (73%-80%), had negative lymph node status (61%-62%), had a tumor size of 2.1-5 cm (55%-58%), and/or pathologic stage II disease (54%-55%).
Survival and safety
At a median follow-up of 56.5 months, the median 5-year DFS rate was 83% in the capecitabine group, compared with 73% in the observation group (P = .027). Similarly, capecitabine use correlated with a significantly better rate of distant DFS (85% vs. 76%; P = .016).
Although the capecitabine group demonstrated a slight trend toward improved OS at 5 years, this finding was not statistically significant (86% vs. 81%; P = .203).
Capecitabine was generally well tolerated, with 91% of patients completing 1 year of therapy, and 75% completing therapy at the full dose.
Almost half of patients in the capecitabine group experienced hand-foot syndrome (45%), and one in four developed leukopenia (24%). Less common adverse events included hyperbilirubinemia (13%), gastrointestinal pain (7%), and elevated serum transaminases (5%). No unexpected serious adverse events occurred.
Effects on practice
Amy Tiersten, MD, of the Icahn School of Medicine at Mount Sinai in New York, suggested these findings may lead to broader use of capecitabine among patients with TNBC.
“[This is a] very exciting study showing an impressive disease-free survival benefit in the adjuvant setting for capecitabine in patients with early stage TNBC,” Dr. Tiersten said. “Presently, we only have positive data for capecitabine in patients with residual disease after neoadjuvant therapy, but this current study now suggests that this benefit could extend to all comers.”
Dr. Tiersten advised that the medical community stay tuned, since longer-term data may provide a clearer picture of survival benefit.
“It will be interesting to see if there is an impact on overall survival with further follow-up,” she said.
According to invited discussant Naamit Kurshan Gerber, MD, of New York University, the results support previous findings from the CREATE-X trial, along with meta-analyses that have shown a “preferential benefit” of capecitabine when used to treat TNBC, compared with estrogen receptor–positive disease.
Still, Dr. Gerber noted that, for most patients, the findings from the SYSUCC-001 trial are unlikely to influence clinical decision-making since most patients with TNBC receive neoadjuvant chemotherapy followed by treatment based on pathologic response. However, she also suggested that, after peer review, the findings could influence treatment for a select few.
“For the small population of patients who receive adjuvant chemotherapy for higher-stage TNBC and who would have met eligibility criteria, this approach may be considered,” Dr. Gerber said.
The study was funded by the Sun Yat-sen University Clinical Research 5010 Program. The investigators disclosed no conflicts of interest. Dr. Gerber reported a relationship with OncLive. Dr. Tiersten reported no relevant disclosures.
SOURCE: Wang X et al. ASCO 2020, Abstract 507.
according to results of a phase 3 trial.
Patients who received metronomic capecitabine maintenance had significantly higher rates of 5-year DFS and distant DFS, but not OS, when compared with patients who did not receive capecitabine, reported Xi Wang, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, who presented the findings as part of the American Society of Clinical Oncology virtual scientific program.
“TNBC has the worst outcomes among all subtypes of breast cancer,” Dr. Wang said. “Effective strategies to reduce risk of relapse are a critical clinical need.”
He went on to describe capecitabine as a “potential ideal drug for metronomic administration,” particularly among patients with high risk of distant metastasis.
With that in mind, Dr. Wang and colleagues tested metronomic capecitabine maintenance in the phase 3 SYSUCC-001 trial. The trial included 434 patients with invasive ductal carcinoma. They had undergone standard therapy, which included surgery, neoadjuvant/adjuvant chemotherapy, and radiation therapy.
Patients were randomized to receive capecitabine at 650 mg/m2 twice daily for 1 year (n = 221) or undergo observation (n = 213). The primary endpoint was DFS, while secondary endpoints included safety, distant DFS, and OS.
According to Dr. Wang, the two patient groups were “well balanced,” with similar baseline characteristics. Most patients underwent adjuvant chemotherapy (93%), had histological grade 3 tumors (71%-74%), had a Ki-67 index of at least 30% (73%-80%), had negative lymph node status (61%-62%), had a tumor size of 2.1-5 cm (55%-58%), and/or pathologic stage II disease (54%-55%).
Survival and safety
At a median follow-up of 56.5 months, the median 5-year DFS rate was 83% in the capecitabine group, compared with 73% in the observation group (P = .027). Similarly, capecitabine use correlated with a significantly better rate of distant DFS (85% vs. 76%; P = .016).
Although the capecitabine group demonstrated a slight trend toward improved OS at 5 years, this finding was not statistically significant (86% vs. 81%; P = .203).
Capecitabine was generally well tolerated, with 91% of patients completing 1 year of therapy, and 75% completing therapy at the full dose.
Almost half of patients in the capecitabine group experienced hand-foot syndrome (45%), and one in four developed leukopenia (24%). Less common adverse events included hyperbilirubinemia (13%), gastrointestinal pain (7%), and elevated serum transaminases (5%). No unexpected serious adverse events occurred.
Effects on practice
Amy Tiersten, MD, of the Icahn School of Medicine at Mount Sinai in New York, suggested these findings may lead to broader use of capecitabine among patients with TNBC.
“[This is a] very exciting study showing an impressive disease-free survival benefit in the adjuvant setting for capecitabine in patients with early stage TNBC,” Dr. Tiersten said. “Presently, we only have positive data for capecitabine in patients with residual disease after neoadjuvant therapy, but this current study now suggests that this benefit could extend to all comers.”
Dr. Tiersten advised that the medical community stay tuned, since longer-term data may provide a clearer picture of survival benefit.
“It will be interesting to see if there is an impact on overall survival with further follow-up,” she said.
According to invited discussant Naamit Kurshan Gerber, MD, of New York University, the results support previous findings from the CREATE-X trial, along with meta-analyses that have shown a “preferential benefit” of capecitabine when used to treat TNBC, compared with estrogen receptor–positive disease.
Still, Dr. Gerber noted that, for most patients, the findings from the SYSUCC-001 trial are unlikely to influence clinical decision-making since most patients with TNBC receive neoadjuvant chemotherapy followed by treatment based on pathologic response. However, she also suggested that, after peer review, the findings could influence treatment for a select few.
“For the small population of patients who receive adjuvant chemotherapy for higher-stage TNBC and who would have met eligibility criteria, this approach may be considered,” Dr. Gerber said.
The study was funded by the Sun Yat-sen University Clinical Research 5010 Program. The investigators disclosed no conflicts of interest. Dr. Gerber reported a relationship with OncLive. Dr. Tiersten reported no relevant disclosures.
SOURCE: Wang X et al. ASCO 2020, Abstract 507.
FROM ASCO 2020
PPI added to chemo improves breast tumor response rate
The proton pump inhibitor (PPI) omeprazole may be a useful addition to treatment for triple-negative breast cancer, as it boosted the expected rate of tumor disappearance among women with early-stage disease, according to the results of a phase 2 trial.
The trial results are presented online at the 2020 virtual annual meeting of the American Society of Clinical Oncology.
The rationale behind the approach includes the fact that PPIs inhibit fatty acid synthase (FASN), an enzyme overexpressed in 70% of newly diagnosed triple-negative breast cancers (TNBC) and associated with poor prognosis.
In the study, omeprazole, a generic drug for gastroesophageal reflux, was added to standard chemotherapy. Both were given to 42 women as neoadjuvant treatment in the weeks before breast surgery at five US centers in the single-arm study.
The pathologic complete response (pCR) rate was 71% in the study population, which is higher than the typical 40% seen in patients treated with standard AC-T (adriamycin and cyclophosphamide plus a taxane), said lead author Sagar D. Sardesai, MBBS, a medical oncologist at Ohio State Comprehensive Cancer Center in Columbus.
“It’s exciting,” said Dr. Sardesai in an interview. “Overall, triple-negative patients who achieve a pCR have a very good outcome.”
That complete disappearance of the tumor is a surrogate for overall survival in TNBC, and patients who achieve it have a greatly reduced risk of recurrence or death, he explained.
Natalie Berger, MD, medical oncologist, Icahn School of Medicine at Mount Sinai, New York City, said the study’s pCR rates were “much higher” than expected and “intriguing and hypothesis generating.”
But Dr. Berger, who was not involved in the study, wanted to see more data.
“Having a non-chemotherapeutic agent to offer our patients with TNBC that improves pCR rates without added toxicity would be an exciting finding, but we need a larger randomized study,” she said in an email.
The researchers, who include high-profile breast cancer specialist Kathy Miller, MD, of Indiana University, are seeking a National Cancer Institute or Department of Defense grant to mount a 100-plus patient randomized trial.
Potential Drug Target for Some Years
Dr. Sardesai explained that FASN, which is an enzyme, helps generate fatty acids that are a key to cancer cell survival. FASN is primarily found in hormone-dominated tissue such as those of the endometrium, prostate, and breast.
PPIs “selectively inhibit FASN activity and induce apoptosis in breast cancer cell lines with minimal effect on non-malignant cells,” wrote the study authors in their meeting abstract.
The only other known agent known to inhibit FASN is the weight loss drug orlistat, which is poorly absorbed by the body and unlikely to impact cancer cells, Dr. Sardesai said.
FASN has been a potential drug target in TNBC for 10 to 15 years, but the first clinical evidence of efficacy in solid tumors was only seen in the last 5 years, he commented.
In 2015, Chinese investigators reported that the PPI esomeprazole in combination with chemotherapy produced a 5-month improvement in progression-free survival (vs. chemo alone) among a subset of 15 TNBC patients in a randomized trial of 94 patients with a variety of breast cancer types.
No Added Toxicity, But Some Unexpected Findings
The study was conducted in patients with early-stage, operable TNBC (with and without baseline FASN expression) and no prior PPI use within 12 months.
All patients started daily high-dose omeprazole 4 to 7 days prior to start of AC-T neoadjuvant chemotherapy (the addition of carboplatin was allowed per physician discretion) and continued until surgery.
The primary endpoint was pCR, defined as no residual invasive disease in breast or axilla, in patients with baseline FASN expression (FASN+). The pCR rate was 71.4% in the 28 FASN+ patients and 71.8% in all 42 enrolled patients. The researchers had targeted a pCR rate of 60% in the FASN+ patients. Also, among the subset of 15 patients who received carboplatin with AC-T, the pCR was 73%.
These two findings both have limitations, commented Dr. Berger. She pointed out that it is “unexplained” as to why the pCR rates were similar among the FASN+ patients and the total population (including 14 FASN– patients); the pCR rate would be expected to be lower in the total population, she suggested.
Further, it was also unexplained as to why there were similar pCR rates with or without carboplatin; other research has demonstrated improved pCR rates in patients receiving additional carboplatin (compared to AC-T alone) but at the cost of increased toxicity, she said.
Dr. Sardesai said that omeprazole was well tolerated with no known grade 3 or 4 toxicities and that the chemotherapy toxicity was similar to prior studies of AC-T. PPIs have side effects if taken for longer than a year, including a higher risk of infections, osteoporosis, and low magnesium, he also commented.
“Omeprazole can be safely administered in doses that inhibit FASN. The addition of high-dose omeprazole to neoadjuvant AC-T yields a promising pCR rate without adding toxicity,” the authors concluded in their abstract.
Dr. Sardesai also highlighted the fact that using a PPI for breast cancer is an example of drug repurposing. The approach offers a way of rapid drug development because PPIs have complete safety and pharmacokinetics data available, he said. “If we can prove the efficacy, the treatment can move forward quickly and be available in clinical practice much sooner than with traditional drug development.”
The study was funded by the Breast Cancer Research Foundation. Dr. Sardesai disclosed financial ties to Novartis and Immunomedics. Other study authors have ties to industry. Dr. Berger disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
The proton pump inhibitor (PPI) omeprazole may be a useful addition to treatment for triple-negative breast cancer, as it boosted the expected rate of tumor disappearance among women with early-stage disease, according to the results of a phase 2 trial.
The trial results are presented online at the 2020 virtual annual meeting of the American Society of Clinical Oncology.
The rationale behind the approach includes the fact that PPIs inhibit fatty acid synthase (FASN), an enzyme overexpressed in 70% of newly diagnosed triple-negative breast cancers (TNBC) and associated with poor prognosis.
In the study, omeprazole, a generic drug for gastroesophageal reflux, was added to standard chemotherapy. Both were given to 42 women as neoadjuvant treatment in the weeks before breast surgery at five US centers in the single-arm study.
The pathologic complete response (pCR) rate was 71% in the study population, which is higher than the typical 40% seen in patients treated with standard AC-T (adriamycin and cyclophosphamide plus a taxane), said lead author Sagar D. Sardesai, MBBS, a medical oncologist at Ohio State Comprehensive Cancer Center in Columbus.
“It’s exciting,” said Dr. Sardesai in an interview. “Overall, triple-negative patients who achieve a pCR have a very good outcome.”
That complete disappearance of the tumor is a surrogate for overall survival in TNBC, and patients who achieve it have a greatly reduced risk of recurrence or death, he explained.
Natalie Berger, MD, medical oncologist, Icahn School of Medicine at Mount Sinai, New York City, said the study’s pCR rates were “much higher” than expected and “intriguing and hypothesis generating.”
But Dr. Berger, who was not involved in the study, wanted to see more data.
“Having a non-chemotherapeutic agent to offer our patients with TNBC that improves pCR rates without added toxicity would be an exciting finding, but we need a larger randomized study,” she said in an email.
The researchers, who include high-profile breast cancer specialist Kathy Miller, MD, of Indiana University, are seeking a National Cancer Institute or Department of Defense grant to mount a 100-plus patient randomized trial.
Potential Drug Target for Some Years
Dr. Sardesai explained that FASN, which is an enzyme, helps generate fatty acids that are a key to cancer cell survival. FASN is primarily found in hormone-dominated tissue such as those of the endometrium, prostate, and breast.
PPIs “selectively inhibit FASN activity and induce apoptosis in breast cancer cell lines with minimal effect on non-malignant cells,” wrote the study authors in their meeting abstract.
The only other known agent known to inhibit FASN is the weight loss drug orlistat, which is poorly absorbed by the body and unlikely to impact cancer cells, Dr. Sardesai said.
FASN has been a potential drug target in TNBC for 10 to 15 years, but the first clinical evidence of efficacy in solid tumors was only seen in the last 5 years, he commented.
In 2015, Chinese investigators reported that the PPI esomeprazole in combination with chemotherapy produced a 5-month improvement in progression-free survival (vs. chemo alone) among a subset of 15 TNBC patients in a randomized trial of 94 patients with a variety of breast cancer types.
No Added Toxicity, But Some Unexpected Findings
The study was conducted in patients with early-stage, operable TNBC (with and without baseline FASN expression) and no prior PPI use within 12 months.
All patients started daily high-dose omeprazole 4 to 7 days prior to start of AC-T neoadjuvant chemotherapy (the addition of carboplatin was allowed per physician discretion) and continued until surgery.
The primary endpoint was pCR, defined as no residual invasive disease in breast or axilla, in patients with baseline FASN expression (FASN+). The pCR rate was 71.4% in the 28 FASN+ patients and 71.8% in all 42 enrolled patients. The researchers had targeted a pCR rate of 60% in the FASN+ patients. Also, among the subset of 15 patients who received carboplatin with AC-T, the pCR was 73%.
These two findings both have limitations, commented Dr. Berger. She pointed out that it is “unexplained” as to why the pCR rates were similar among the FASN+ patients and the total population (including 14 FASN– patients); the pCR rate would be expected to be lower in the total population, she suggested.
Further, it was also unexplained as to why there were similar pCR rates with or without carboplatin; other research has demonstrated improved pCR rates in patients receiving additional carboplatin (compared to AC-T alone) but at the cost of increased toxicity, she said.
Dr. Sardesai said that omeprazole was well tolerated with no known grade 3 or 4 toxicities and that the chemotherapy toxicity was similar to prior studies of AC-T. PPIs have side effects if taken for longer than a year, including a higher risk of infections, osteoporosis, and low magnesium, he also commented.
“Omeprazole can be safely administered in doses that inhibit FASN. The addition of high-dose omeprazole to neoadjuvant AC-T yields a promising pCR rate without adding toxicity,” the authors concluded in their abstract.
Dr. Sardesai also highlighted the fact that using a PPI for breast cancer is an example of drug repurposing. The approach offers a way of rapid drug development because PPIs have complete safety and pharmacokinetics data available, he said. “If we can prove the efficacy, the treatment can move forward quickly and be available in clinical practice much sooner than with traditional drug development.”
The study was funded by the Breast Cancer Research Foundation. Dr. Sardesai disclosed financial ties to Novartis and Immunomedics. Other study authors have ties to industry. Dr. Berger disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
The proton pump inhibitor (PPI) omeprazole may be a useful addition to treatment for triple-negative breast cancer, as it boosted the expected rate of tumor disappearance among women with early-stage disease, according to the results of a phase 2 trial.
The trial results are presented online at the 2020 virtual annual meeting of the American Society of Clinical Oncology.
The rationale behind the approach includes the fact that PPIs inhibit fatty acid synthase (FASN), an enzyme overexpressed in 70% of newly diagnosed triple-negative breast cancers (TNBC) and associated with poor prognosis.
In the study, omeprazole, a generic drug for gastroesophageal reflux, was added to standard chemotherapy. Both were given to 42 women as neoadjuvant treatment in the weeks before breast surgery at five US centers in the single-arm study.
The pathologic complete response (pCR) rate was 71% in the study population, which is higher than the typical 40% seen in patients treated with standard AC-T (adriamycin and cyclophosphamide plus a taxane), said lead author Sagar D. Sardesai, MBBS, a medical oncologist at Ohio State Comprehensive Cancer Center in Columbus.
“It’s exciting,” said Dr. Sardesai in an interview. “Overall, triple-negative patients who achieve a pCR have a very good outcome.”
That complete disappearance of the tumor is a surrogate for overall survival in TNBC, and patients who achieve it have a greatly reduced risk of recurrence or death, he explained.
Natalie Berger, MD, medical oncologist, Icahn School of Medicine at Mount Sinai, New York City, said the study’s pCR rates were “much higher” than expected and “intriguing and hypothesis generating.”
But Dr. Berger, who was not involved in the study, wanted to see more data.
“Having a non-chemotherapeutic agent to offer our patients with TNBC that improves pCR rates without added toxicity would be an exciting finding, but we need a larger randomized study,” she said in an email.
The researchers, who include high-profile breast cancer specialist Kathy Miller, MD, of Indiana University, are seeking a National Cancer Institute or Department of Defense grant to mount a 100-plus patient randomized trial.
Potential Drug Target for Some Years
Dr. Sardesai explained that FASN, which is an enzyme, helps generate fatty acids that are a key to cancer cell survival. FASN is primarily found in hormone-dominated tissue such as those of the endometrium, prostate, and breast.
PPIs “selectively inhibit FASN activity and induce apoptosis in breast cancer cell lines with minimal effect on non-malignant cells,” wrote the study authors in their meeting abstract.
The only other known agent known to inhibit FASN is the weight loss drug orlistat, which is poorly absorbed by the body and unlikely to impact cancer cells, Dr. Sardesai said.
FASN has been a potential drug target in TNBC for 10 to 15 years, but the first clinical evidence of efficacy in solid tumors was only seen in the last 5 years, he commented.
In 2015, Chinese investigators reported that the PPI esomeprazole in combination with chemotherapy produced a 5-month improvement in progression-free survival (vs. chemo alone) among a subset of 15 TNBC patients in a randomized trial of 94 patients with a variety of breast cancer types.
No Added Toxicity, But Some Unexpected Findings
The study was conducted in patients with early-stage, operable TNBC (with and without baseline FASN expression) and no prior PPI use within 12 months.
All patients started daily high-dose omeprazole 4 to 7 days prior to start of AC-T neoadjuvant chemotherapy (the addition of carboplatin was allowed per physician discretion) and continued until surgery.
The primary endpoint was pCR, defined as no residual invasive disease in breast or axilla, in patients with baseline FASN expression (FASN+). The pCR rate was 71.4% in the 28 FASN+ patients and 71.8% in all 42 enrolled patients. The researchers had targeted a pCR rate of 60% in the FASN+ patients. Also, among the subset of 15 patients who received carboplatin with AC-T, the pCR was 73%.
These two findings both have limitations, commented Dr. Berger. She pointed out that it is “unexplained” as to why the pCR rates were similar among the FASN+ patients and the total population (including 14 FASN– patients); the pCR rate would be expected to be lower in the total population, she suggested.
Further, it was also unexplained as to why there were similar pCR rates with or without carboplatin; other research has demonstrated improved pCR rates in patients receiving additional carboplatin (compared to AC-T alone) but at the cost of increased toxicity, she said.
Dr. Sardesai said that omeprazole was well tolerated with no known grade 3 or 4 toxicities and that the chemotherapy toxicity was similar to prior studies of AC-T. PPIs have side effects if taken for longer than a year, including a higher risk of infections, osteoporosis, and low magnesium, he also commented.
“Omeprazole can be safely administered in doses that inhibit FASN. The addition of high-dose omeprazole to neoadjuvant AC-T yields a promising pCR rate without adding toxicity,” the authors concluded in their abstract.
Dr. Sardesai also highlighted the fact that using a PPI for breast cancer is an example of drug repurposing. The approach offers a way of rapid drug development because PPIs have complete safety and pharmacokinetics data available, he said. “If we can prove the efficacy, the treatment can move forward quickly and be available in clinical practice much sooner than with traditional drug development.”
The study was funded by the Breast Cancer Research Foundation. Dr. Sardesai disclosed financial ties to Novartis and Immunomedics. Other study authors have ties to industry. Dr. Berger disclosed no relevant financial relationships.
This article first appeared on Medscape.com.
FROM ASCO 2020
First-line nivolumab plus platinum/etoposide effective in extensive-stage SCLC
While nivolumab plus doublet chemotherapy was effective in extensive-stage small-cell lung cancer (ES-SCLC) in a recent randomized trial, the results might not be sufficient to change current clinical practice, in which two first-line chemo-immunotherapies are already approved and recommended, sources said.
Nivolumab added to platinum/etoposide doublet chemotherapy was well tolerated and significantly improved progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone, according to results of ECOG-ACRIN EA5161, a randomized, phase 2 trial including 160 patients with ES-SCLC.
Risks of progression and death were reduced by 32% and 27%, respectively, when the immune checkpoint inhibitor was given along with chemotherapy, according to data presented by investigator Ticiana A. Leal, MD, of the University of Wisconsin Carbone Cancer Center in Madison.
“Our study, EA5161, confirms the efficacy of nivolumab in extensive-stage small cell lung cancer,” Dr. Leal said in a presentation she gave as part of the American Society of Clinical Oncology virtual scientific program.
Nivolumab did demonstrate a clear PFS advantage in EA5161, but “more surprisingly for a small trial” it also showed a clear OS advantage, said Taofeek K. Owonikoko, MD, PhD, in a commentary on the study.
“While the study as currently reported is insufficient to change practice, it does however provide very strong data to make the combination of nivolumab and platinum doublet acceptable as a platform for future clinical trials,” he said in the commentary, which was also included in the virtual ASCO proceedings.
Going forward, it would be difficult to justify another nondefinitive randomized phase 2 chemo-immunotherapy trial, especially if there are no “immediate plans” for a confirmatory phase 3 trial, added Dr. Owonikoko, who is director of thoracic oncology at Winship Cancer Institute of Emory University in Atlanta.
Nivolumab wasn’t the only immune checkpoint with new first-line data in ES-SCLC at ASCO. In the randomized, double-blind, phase 3 KEYNOTE-604 trial, pembrolizumab added to etoposide and platinum significantly prolonged PFS and showed a trend toward improved OS. However, the significance threshold for OS was missed, according to the report.
While these pembrolizumab data are also insufficient to change today’s practice standards, results for both the pembrolizumab- and nivolumab-containing regimens are nevertheless compelling to support their use as a platform for new treatment strategies, according to Dr. Owonikoko.
With these new ASCO data, there are now randomized data confirming a benefit of immune checkpoint inhibitor–based regimens in ES-SCLC, according to Lauren A. Byers, MD, from the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston.
Immune checkpoint inhibitors that are approved by the Food and Drug Administration for first-line treatment of ES-SCLC include atezolizumab (in combination with carboplatin and etoposide) and durvalumab (in combination with either carboplatin or cisplatin plus etoposide). In current National Comprehensive Cancer Network (NCCN) guidelines, both are described as “preferred” regimens for primary or adjuvant therapy.
“A lot of times in oncology we have trials with similar drugs, and you get somewhat different answers in terms of the outcome of the trials, so we’re kind of trying to tease them apart,” Dr. Byers said in an interview.
“I think in this situation, we’ve got four studies, and they essentially are extremely similar in terms of the result, which just gives us even more confidence that there is benefit, at least for a subset of patients.”
The EA5161 study was developed to evaluate the role of nivolumab in ES-SCLC, Dr. Leal said in her virtual ASCO presentation.
Of the 160 patients enrolled and randomized, 145 were eligible and treated, including 75 in the nivolumab plus chemotherapy arm and 70 in the chemotherapy arm. Participants were evenly split between performance status 0 and 1, and little more than half of patients were women, and a median of five treatment cycles were delivered in each arm.
Median PFS, the primary end point of the trial, was 5.5 months for nivolumab plus chemotherapy versus 4.7 months for chemotherapy alone for all eligible and treated patients (hazard ratio, 0.68; 95% confidence interval, 0.48-1.00; P = .047). In the intent-to-treat population, median PFS was 5.5 and 4.6 months in the respective arms (HR, 0.65; 95% CI, 0.46-0.91; P = .012).
Median overall survival was 11.3 months and 9.3 months for the nivolumab plus chemotherapy and chemotherapy-only arms, respectively, for all eligible and treated patients (HR, 0.73; 95% CI, 0.49-1.1), and in the intent-to-treat population, median OS was 11.3 and 8.5 months for the respective arms (HR, 0.67; 95% CI, 0.46-0.98; P = .038).
The overall response rate was 52% for nivolumab plus chemotherapy and 47% for chemotherapy alone, with a median duration of response of 5.6 and 3.3 months, respectively, Dr. Leal reported.
Treatment was generally well tolerated in both arms, according to the investigator, with no safety signals observed. Toxicities resulting in death occurred in nine patients in the nivolumab plus chemotherapy arm and seven in the chemotherapy-only arm. “Most of the events were related to progression of disease,” Dr. Leal said.
While nivolumab and pembrolizumab’s use in the first-line setting may be uncertain, it is currently approved for metastatic SCLC that has progressed following platinum-based chemotherapy and at least one more line of therapy, according to the drug’s package insert.
The EA5161 study was sponsored by the National Cancer Institute. Dr. Leal provided disclosures related to AbbVie, AstraZeneca, Bayer, BeyondSpring, Bristol-Myers Squibb, Genentech, InvisionFirst Lung, Merck, Mirati, Novocure, and Takeda.
Dr. Owonikoko provided disclosures related to Bristol-Myers Squibb, Novartis, Celgene, Lilly, Sandoz, AbbVie, Eisai, and Takeda, among others. Dr. Byers reported disclosures related to Bristol-Myers Squibb, AstraZeneca, AbbVie, GenMab, PharmaMar, and Sierra Oncology, Tolero, Alethia, Merck, Jazz Pharmaceuticals, and Pfizer.
SOURCE: Leal TA et al. ASCO 2020, Abstract 9000.
While nivolumab plus doublet chemotherapy was effective in extensive-stage small-cell lung cancer (ES-SCLC) in a recent randomized trial, the results might not be sufficient to change current clinical practice, in which two first-line chemo-immunotherapies are already approved and recommended, sources said.
Nivolumab added to platinum/etoposide doublet chemotherapy was well tolerated and significantly improved progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone, according to results of ECOG-ACRIN EA5161, a randomized, phase 2 trial including 160 patients with ES-SCLC.
Risks of progression and death were reduced by 32% and 27%, respectively, when the immune checkpoint inhibitor was given along with chemotherapy, according to data presented by investigator Ticiana A. Leal, MD, of the University of Wisconsin Carbone Cancer Center in Madison.
“Our study, EA5161, confirms the efficacy of nivolumab in extensive-stage small cell lung cancer,” Dr. Leal said in a presentation she gave as part of the American Society of Clinical Oncology virtual scientific program.
Nivolumab did demonstrate a clear PFS advantage in EA5161, but “more surprisingly for a small trial” it also showed a clear OS advantage, said Taofeek K. Owonikoko, MD, PhD, in a commentary on the study.
“While the study as currently reported is insufficient to change practice, it does however provide very strong data to make the combination of nivolumab and platinum doublet acceptable as a platform for future clinical trials,” he said in the commentary, which was also included in the virtual ASCO proceedings.
Going forward, it would be difficult to justify another nondefinitive randomized phase 2 chemo-immunotherapy trial, especially if there are no “immediate plans” for a confirmatory phase 3 trial, added Dr. Owonikoko, who is director of thoracic oncology at Winship Cancer Institute of Emory University in Atlanta.
Nivolumab wasn’t the only immune checkpoint with new first-line data in ES-SCLC at ASCO. In the randomized, double-blind, phase 3 KEYNOTE-604 trial, pembrolizumab added to etoposide and platinum significantly prolonged PFS and showed a trend toward improved OS. However, the significance threshold for OS was missed, according to the report.
While these pembrolizumab data are also insufficient to change today’s practice standards, results for both the pembrolizumab- and nivolumab-containing regimens are nevertheless compelling to support their use as a platform for new treatment strategies, according to Dr. Owonikoko.
With these new ASCO data, there are now randomized data confirming a benefit of immune checkpoint inhibitor–based regimens in ES-SCLC, according to Lauren A. Byers, MD, from the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston.
Immune checkpoint inhibitors that are approved by the Food and Drug Administration for first-line treatment of ES-SCLC include atezolizumab (in combination with carboplatin and etoposide) and durvalumab (in combination with either carboplatin or cisplatin plus etoposide). In current National Comprehensive Cancer Network (NCCN) guidelines, both are described as “preferred” regimens for primary or adjuvant therapy.
“A lot of times in oncology we have trials with similar drugs, and you get somewhat different answers in terms of the outcome of the trials, so we’re kind of trying to tease them apart,” Dr. Byers said in an interview.
“I think in this situation, we’ve got four studies, and they essentially are extremely similar in terms of the result, which just gives us even more confidence that there is benefit, at least for a subset of patients.”
The EA5161 study was developed to evaluate the role of nivolumab in ES-SCLC, Dr. Leal said in her virtual ASCO presentation.
Of the 160 patients enrolled and randomized, 145 were eligible and treated, including 75 in the nivolumab plus chemotherapy arm and 70 in the chemotherapy arm. Participants were evenly split between performance status 0 and 1, and little more than half of patients were women, and a median of five treatment cycles were delivered in each arm.
Median PFS, the primary end point of the trial, was 5.5 months for nivolumab plus chemotherapy versus 4.7 months for chemotherapy alone for all eligible and treated patients (hazard ratio, 0.68; 95% confidence interval, 0.48-1.00; P = .047). In the intent-to-treat population, median PFS was 5.5 and 4.6 months in the respective arms (HR, 0.65; 95% CI, 0.46-0.91; P = .012).
Median overall survival was 11.3 months and 9.3 months for the nivolumab plus chemotherapy and chemotherapy-only arms, respectively, for all eligible and treated patients (HR, 0.73; 95% CI, 0.49-1.1), and in the intent-to-treat population, median OS was 11.3 and 8.5 months for the respective arms (HR, 0.67; 95% CI, 0.46-0.98; P = .038).
The overall response rate was 52% for nivolumab plus chemotherapy and 47% for chemotherapy alone, with a median duration of response of 5.6 and 3.3 months, respectively, Dr. Leal reported.
Treatment was generally well tolerated in both arms, according to the investigator, with no safety signals observed. Toxicities resulting in death occurred in nine patients in the nivolumab plus chemotherapy arm and seven in the chemotherapy-only arm. “Most of the events were related to progression of disease,” Dr. Leal said.
While nivolumab and pembrolizumab’s use in the first-line setting may be uncertain, it is currently approved for metastatic SCLC that has progressed following platinum-based chemotherapy and at least one more line of therapy, according to the drug’s package insert.
The EA5161 study was sponsored by the National Cancer Institute. Dr. Leal provided disclosures related to AbbVie, AstraZeneca, Bayer, BeyondSpring, Bristol-Myers Squibb, Genentech, InvisionFirst Lung, Merck, Mirati, Novocure, and Takeda.
Dr. Owonikoko provided disclosures related to Bristol-Myers Squibb, Novartis, Celgene, Lilly, Sandoz, AbbVie, Eisai, and Takeda, among others. Dr. Byers reported disclosures related to Bristol-Myers Squibb, AstraZeneca, AbbVie, GenMab, PharmaMar, and Sierra Oncology, Tolero, Alethia, Merck, Jazz Pharmaceuticals, and Pfizer.
SOURCE: Leal TA et al. ASCO 2020, Abstract 9000.
While nivolumab plus doublet chemotherapy was effective in extensive-stage small-cell lung cancer (ES-SCLC) in a recent randomized trial, the results might not be sufficient to change current clinical practice, in which two first-line chemo-immunotherapies are already approved and recommended, sources said.
Nivolumab added to platinum/etoposide doublet chemotherapy was well tolerated and significantly improved progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone, according to results of ECOG-ACRIN EA5161, a randomized, phase 2 trial including 160 patients with ES-SCLC.
Risks of progression and death were reduced by 32% and 27%, respectively, when the immune checkpoint inhibitor was given along with chemotherapy, according to data presented by investigator Ticiana A. Leal, MD, of the University of Wisconsin Carbone Cancer Center in Madison.
“Our study, EA5161, confirms the efficacy of nivolumab in extensive-stage small cell lung cancer,” Dr. Leal said in a presentation she gave as part of the American Society of Clinical Oncology virtual scientific program.
Nivolumab did demonstrate a clear PFS advantage in EA5161, but “more surprisingly for a small trial” it also showed a clear OS advantage, said Taofeek K. Owonikoko, MD, PhD, in a commentary on the study.
“While the study as currently reported is insufficient to change practice, it does however provide very strong data to make the combination of nivolumab and platinum doublet acceptable as a platform for future clinical trials,” he said in the commentary, which was also included in the virtual ASCO proceedings.
Going forward, it would be difficult to justify another nondefinitive randomized phase 2 chemo-immunotherapy trial, especially if there are no “immediate plans” for a confirmatory phase 3 trial, added Dr. Owonikoko, who is director of thoracic oncology at Winship Cancer Institute of Emory University in Atlanta.
Nivolumab wasn’t the only immune checkpoint with new first-line data in ES-SCLC at ASCO. In the randomized, double-blind, phase 3 KEYNOTE-604 trial, pembrolizumab added to etoposide and platinum significantly prolonged PFS and showed a trend toward improved OS. However, the significance threshold for OS was missed, according to the report.
While these pembrolizumab data are also insufficient to change today’s practice standards, results for both the pembrolizumab- and nivolumab-containing regimens are nevertheless compelling to support their use as a platform for new treatment strategies, according to Dr. Owonikoko.
With these new ASCO data, there are now randomized data confirming a benefit of immune checkpoint inhibitor–based regimens in ES-SCLC, according to Lauren A. Byers, MD, from the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center in Houston.
Immune checkpoint inhibitors that are approved by the Food and Drug Administration for first-line treatment of ES-SCLC include atezolizumab (in combination with carboplatin and etoposide) and durvalumab (in combination with either carboplatin or cisplatin plus etoposide). In current National Comprehensive Cancer Network (NCCN) guidelines, both are described as “preferred” regimens for primary or adjuvant therapy.
“A lot of times in oncology we have trials with similar drugs, and you get somewhat different answers in terms of the outcome of the trials, so we’re kind of trying to tease them apart,” Dr. Byers said in an interview.
“I think in this situation, we’ve got four studies, and they essentially are extremely similar in terms of the result, which just gives us even more confidence that there is benefit, at least for a subset of patients.”
The EA5161 study was developed to evaluate the role of nivolumab in ES-SCLC, Dr. Leal said in her virtual ASCO presentation.
Of the 160 patients enrolled and randomized, 145 were eligible and treated, including 75 in the nivolumab plus chemotherapy arm and 70 in the chemotherapy arm. Participants were evenly split between performance status 0 and 1, and little more than half of patients were women, and a median of five treatment cycles were delivered in each arm.
Median PFS, the primary end point of the trial, was 5.5 months for nivolumab plus chemotherapy versus 4.7 months for chemotherapy alone for all eligible and treated patients (hazard ratio, 0.68; 95% confidence interval, 0.48-1.00; P = .047). In the intent-to-treat population, median PFS was 5.5 and 4.6 months in the respective arms (HR, 0.65; 95% CI, 0.46-0.91; P = .012).
Median overall survival was 11.3 months and 9.3 months for the nivolumab plus chemotherapy and chemotherapy-only arms, respectively, for all eligible and treated patients (HR, 0.73; 95% CI, 0.49-1.1), and in the intent-to-treat population, median OS was 11.3 and 8.5 months for the respective arms (HR, 0.67; 95% CI, 0.46-0.98; P = .038).
The overall response rate was 52% for nivolumab plus chemotherapy and 47% for chemotherapy alone, with a median duration of response of 5.6 and 3.3 months, respectively, Dr. Leal reported.
Treatment was generally well tolerated in both arms, according to the investigator, with no safety signals observed. Toxicities resulting in death occurred in nine patients in the nivolumab plus chemotherapy arm and seven in the chemotherapy-only arm. “Most of the events were related to progression of disease,” Dr. Leal said.
While nivolumab and pembrolizumab’s use in the first-line setting may be uncertain, it is currently approved for metastatic SCLC that has progressed following platinum-based chemotherapy and at least one more line of therapy, according to the drug’s package insert.
The EA5161 study was sponsored by the National Cancer Institute. Dr. Leal provided disclosures related to AbbVie, AstraZeneca, Bayer, BeyondSpring, Bristol-Myers Squibb, Genentech, InvisionFirst Lung, Merck, Mirati, Novocure, and Takeda.
Dr. Owonikoko provided disclosures related to Bristol-Myers Squibb, Novartis, Celgene, Lilly, Sandoz, AbbVie, Eisai, and Takeda, among others. Dr. Byers reported disclosures related to Bristol-Myers Squibb, AstraZeneca, AbbVie, GenMab, PharmaMar, and Sierra Oncology, Tolero, Alethia, Merck, Jazz Pharmaceuticals, and Pfizer.
SOURCE: Leal TA et al. ASCO 2020, Abstract 9000.
FROM ASCO 2020
Despite guidelines, controversy remains over corticosteroids in COVID-19
Three main reasons have been put forth for using corticosteroids in critically ill patients with COVID-19, but only one – the hope of preventing lung fibrosis in patients with unresolved acute respiratory distress syndrome – is reasonable to employ now outside of formal randomized trials, Peter Pickkers, MD, PhD, asserted at a webinar on COVID-19 sponsored by the European Society of Intensive Care Medicine.
The most commonly invoked rationale for giving steroids in patients with severe COVID-19 is to modulate the destructive inflammatory immune response that occurs with advancing disease. Another justification cited for giving steroids is to treat suspected adrenal insufficiency in those with refractory shock. Of note, both practices are endorsed in the recent Surviving Sepsis Campaign guidelines on management of critically ill patients with COVID-19 (Intensive Care Med. 2020 May;46[5]:854-87).
But those recommendations – numbers 22 and 42 out of a total of 50 recommendations included in the guidelines – should never have been made, according to Dr. Pickkers, professor of experimental intensive care medicine at Radboud University Medical Center in Nijmegen, the Netherlands.
Dueling guidelines
The Surviving Sepsis Campaign guidelines, which were developed by a panel comprising 36 experts in 12 countries, are quite frank in conceding that the guidance in favor of corticosteroids are weak recommendations based on low-quality evidence.
The guidelines recommend against using corticosteroids to try to modulate the immune system in mechanically ventilated COVID-19 patients without acute respiratory distress syndrome (ARDS), but do recommend steroids in those with COVID-19 and ARDS. However, the guidelines also note that, because of the very low quality of the evidence, some experts on the panel preferred not to issue a pro-steroids recommendation at all until higher-quality evidence becomes available. Dr. Pickkers said he believes that the minority view should have prevailed. Moreover, current COVID-19 guidance from the World Health Organization is at odds with the Surviving Sepsis Campaign recommendations; the WHO advises against corticosteroids unless the treatment is indicated for a reason other than immunomodulation, he noted.
The evidence in favor of steroids in an effort to blunt the immune response in COVID patients with ARDS is based largely upon a single small, retrospective, non–peer-reviewed report that 5-7 days of treatment with 1-2 mg/kg per day of methylprednisolone was associated with shortened fever duration and need for supplemental oxygen.
The evidence against steroids for immunomodulation comes mainly from earlier studies of the SARS and MERS novel coronaviruses. For example, in a multicenter study of 309 patients with the MERS (Middle East respiratory syndrome) virus, those who received corticosteroids received no benefit and experienced delayed viral clearance (Am J Respir Crit Care Med. 2018 Mar 15;197[6]:757-67).
“The thing is, virtually all COVID-19 patients in the ICU fulfill the criteria for ARDS, so following the Surviving Sepsis Campaign guidelines would have far-reaching consequences,” Dr. Pickkers said.
Those consequences include a theoretic potential for serious harm arising from dampening the immune response at a point in the course of COVID-19 when the virus is still present, which could result in slowed viral clearance and prolonged viral shedding. Moreover so far no one has been able to identify a sweet spot in the disease course where the viral load has waned and the immune response is sufficiently early that intervention with corticosteroids might have an optimal benefit/risk ratio, he continued.
“My opinion is that at this moment there is no benefit at all for corticosteroids for immunomodulation in patients with COVID-19,” Dr. Pickkers said. “My personal recommendation, in contrast to the Surviving Sepsis Campaign recommendation, is not to use this therapy outside of a study.”
He added that randomized, controlled trials of corticosteroid therapy in critically ill patients with COVID-19 are ongoing in Europe and the United States, including the large RECOVERY study of dexamethasone in the United Kingdom.
As for the Surviving Sepsis Campaign recommendation to use corticosteroids to treat refractory shock in COVID-19, Dr. Pickkers dismissed this guidance as largely irrelevant. That’s because few patients with COVID-19 who need mechanical ventilation have refractory shock as evidenced by the need for a high infusion rate of norepinephrine. Anyway, he noted, that Surviving Sepsis recommendation is based upon extrapolation from evidence of benefit in bacterial septic shock patients, which he deemed to be of questionable relevance to the COVID-19 pandemic.
Attacking the fibroproliferative phase of ARDS
First off, Dr. Pickkers conceded, there is no evidence that treatment with corticosteroids to prevent lung fibrosis in COVID-19 patients with nonresolving ARDS is an effective strategy; the pandemic is simply too new at this point for the appropriate studies to have been done. But this much is known: Postmortem pathologic studies show fibroplastic proliferation is present in the lungs of COVID-19 patients, as in those who die of ARDS of other causes. Also, COVID-19 patients typically aren’t admitted to the ICU until day 11 or 12 after developing their first symptoms, so by the time they display indications that their ARDS is not resolving, the virus has typically left the scene; thus, there is little risk at that point that corticosteroids will promote viral proliferation. Additionally, studies in critically ill patients with nonresolving ARDS of other causes show clinically meaningful benefits for corticosteroid therapy.
Dr. Pickkers cited as “must reading” an analysis of five randomized trials of corticosteroid therapy in a total of 518 patients with acute lung injury ARDS of non–COVID-19 origin. The analysis by investigators at the University of Tennessee, Memphis, concluded that treatment resulted in clinically meaningful reductions in duration of mechanical ventilation and ICU length of stay. Moreover, in the 400 patients whose steroid therapy commenced before day 14 of ARDS, there was a statistically significant 22% reduction in risk of death, compared with patients in whom corticosteroids were started later (Intensive Care Med. 2008 Jan;34[1]:61-9).
Session cochair Jan De Waele, MD, PhD, struck a cautious note, remarking, “It’s my perception that we’re using the evidence that we’ve gathered in other conditions and are now trying to apply it in COVID-19. But quality data on patients with COVID-19 itself is pretty scare, and it’s really hard to say whether this disease behaves similarly to bacterial septic shock or to other viral infections.”
“We need more information about the use of corticosteroids in COVID-19, although I think a lot of people are using it at this moment,” added Dr. De Waele, a surgical intensivist at Ghent (Belgium) University.
That being said, he asked Dr. Pickkers when he considers using corticosteroids to prevent pulmonary fibrosis.
Dr. Pickkers said that when he notices that a COVID-19 patient’s lung compliance is worsening, that stiff lung is a clue that fibrosis is occurring and is having clinical consequences. “We also measure blood procollagen, a not very sensitive but moderately specific marker of fibroproliferation. If we see an increase in this biomarker and the lung mechanics are changing, then we do treat these patients with corticosteroids,” Dr. Pickkers replied.
He and his colleagues try to start steroids before day 14 of ARDS, and they continue treatment for longer than 7 days in order to prevent a rebound inflammatory response upon treatment discontinuation. They also avoid using neuromuscular agents and engage in meticulous infection surveillance in order to minimize potential complications of corticosteroid therapy in the ICU.
Dr. Pickkers reported having no financial conflicts regarding his presentation.
Three main reasons have been put forth for using corticosteroids in critically ill patients with COVID-19, but only one – the hope of preventing lung fibrosis in patients with unresolved acute respiratory distress syndrome – is reasonable to employ now outside of formal randomized trials, Peter Pickkers, MD, PhD, asserted at a webinar on COVID-19 sponsored by the European Society of Intensive Care Medicine.
The most commonly invoked rationale for giving steroids in patients with severe COVID-19 is to modulate the destructive inflammatory immune response that occurs with advancing disease. Another justification cited for giving steroids is to treat suspected adrenal insufficiency in those with refractory shock. Of note, both practices are endorsed in the recent Surviving Sepsis Campaign guidelines on management of critically ill patients with COVID-19 (Intensive Care Med. 2020 May;46[5]:854-87).
But those recommendations – numbers 22 and 42 out of a total of 50 recommendations included in the guidelines – should never have been made, according to Dr. Pickkers, professor of experimental intensive care medicine at Radboud University Medical Center in Nijmegen, the Netherlands.
Dueling guidelines
The Surviving Sepsis Campaign guidelines, which were developed by a panel comprising 36 experts in 12 countries, are quite frank in conceding that the guidance in favor of corticosteroids are weak recommendations based on low-quality evidence.
The guidelines recommend against using corticosteroids to try to modulate the immune system in mechanically ventilated COVID-19 patients without acute respiratory distress syndrome (ARDS), but do recommend steroids in those with COVID-19 and ARDS. However, the guidelines also note that, because of the very low quality of the evidence, some experts on the panel preferred not to issue a pro-steroids recommendation at all until higher-quality evidence becomes available. Dr. Pickkers said he believes that the minority view should have prevailed. Moreover, current COVID-19 guidance from the World Health Organization is at odds with the Surviving Sepsis Campaign recommendations; the WHO advises against corticosteroids unless the treatment is indicated for a reason other than immunomodulation, he noted.
The evidence in favor of steroids in an effort to blunt the immune response in COVID patients with ARDS is based largely upon a single small, retrospective, non–peer-reviewed report that 5-7 days of treatment with 1-2 mg/kg per day of methylprednisolone was associated with shortened fever duration and need for supplemental oxygen.
The evidence against steroids for immunomodulation comes mainly from earlier studies of the SARS and MERS novel coronaviruses. For example, in a multicenter study of 309 patients with the MERS (Middle East respiratory syndrome) virus, those who received corticosteroids received no benefit and experienced delayed viral clearance (Am J Respir Crit Care Med. 2018 Mar 15;197[6]:757-67).
“The thing is, virtually all COVID-19 patients in the ICU fulfill the criteria for ARDS, so following the Surviving Sepsis Campaign guidelines would have far-reaching consequences,” Dr. Pickkers said.
Those consequences include a theoretic potential for serious harm arising from dampening the immune response at a point in the course of COVID-19 when the virus is still present, which could result in slowed viral clearance and prolonged viral shedding. Moreover so far no one has been able to identify a sweet spot in the disease course where the viral load has waned and the immune response is sufficiently early that intervention with corticosteroids might have an optimal benefit/risk ratio, he continued.
“My opinion is that at this moment there is no benefit at all for corticosteroids for immunomodulation in patients with COVID-19,” Dr. Pickkers said. “My personal recommendation, in contrast to the Surviving Sepsis Campaign recommendation, is not to use this therapy outside of a study.”
He added that randomized, controlled trials of corticosteroid therapy in critically ill patients with COVID-19 are ongoing in Europe and the United States, including the large RECOVERY study of dexamethasone in the United Kingdom.
As for the Surviving Sepsis Campaign recommendation to use corticosteroids to treat refractory shock in COVID-19, Dr. Pickkers dismissed this guidance as largely irrelevant. That’s because few patients with COVID-19 who need mechanical ventilation have refractory shock as evidenced by the need for a high infusion rate of norepinephrine. Anyway, he noted, that Surviving Sepsis recommendation is based upon extrapolation from evidence of benefit in bacterial septic shock patients, which he deemed to be of questionable relevance to the COVID-19 pandemic.
Attacking the fibroproliferative phase of ARDS
First off, Dr. Pickkers conceded, there is no evidence that treatment with corticosteroids to prevent lung fibrosis in COVID-19 patients with nonresolving ARDS is an effective strategy; the pandemic is simply too new at this point for the appropriate studies to have been done. But this much is known: Postmortem pathologic studies show fibroplastic proliferation is present in the lungs of COVID-19 patients, as in those who die of ARDS of other causes. Also, COVID-19 patients typically aren’t admitted to the ICU until day 11 or 12 after developing their first symptoms, so by the time they display indications that their ARDS is not resolving, the virus has typically left the scene; thus, there is little risk at that point that corticosteroids will promote viral proliferation. Additionally, studies in critically ill patients with nonresolving ARDS of other causes show clinically meaningful benefits for corticosteroid therapy.
Dr. Pickkers cited as “must reading” an analysis of five randomized trials of corticosteroid therapy in a total of 518 patients with acute lung injury ARDS of non–COVID-19 origin. The analysis by investigators at the University of Tennessee, Memphis, concluded that treatment resulted in clinically meaningful reductions in duration of mechanical ventilation and ICU length of stay. Moreover, in the 400 patients whose steroid therapy commenced before day 14 of ARDS, there was a statistically significant 22% reduction in risk of death, compared with patients in whom corticosteroids were started later (Intensive Care Med. 2008 Jan;34[1]:61-9).
Session cochair Jan De Waele, MD, PhD, struck a cautious note, remarking, “It’s my perception that we’re using the evidence that we’ve gathered in other conditions and are now trying to apply it in COVID-19. But quality data on patients with COVID-19 itself is pretty scare, and it’s really hard to say whether this disease behaves similarly to bacterial septic shock or to other viral infections.”
“We need more information about the use of corticosteroids in COVID-19, although I think a lot of people are using it at this moment,” added Dr. De Waele, a surgical intensivist at Ghent (Belgium) University.
That being said, he asked Dr. Pickkers when he considers using corticosteroids to prevent pulmonary fibrosis.
Dr. Pickkers said that when he notices that a COVID-19 patient’s lung compliance is worsening, that stiff lung is a clue that fibrosis is occurring and is having clinical consequences. “We also measure blood procollagen, a not very sensitive but moderately specific marker of fibroproliferation. If we see an increase in this biomarker and the lung mechanics are changing, then we do treat these patients with corticosteroids,” Dr. Pickkers replied.
He and his colleagues try to start steroids before day 14 of ARDS, and they continue treatment for longer than 7 days in order to prevent a rebound inflammatory response upon treatment discontinuation. They also avoid using neuromuscular agents and engage in meticulous infection surveillance in order to minimize potential complications of corticosteroid therapy in the ICU.
Dr. Pickkers reported having no financial conflicts regarding his presentation.
Three main reasons have been put forth for using corticosteroids in critically ill patients with COVID-19, but only one – the hope of preventing lung fibrosis in patients with unresolved acute respiratory distress syndrome – is reasonable to employ now outside of formal randomized trials, Peter Pickkers, MD, PhD, asserted at a webinar on COVID-19 sponsored by the European Society of Intensive Care Medicine.
The most commonly invoked rationale for giving steroids in patients with severe COVID-19 is to modulate the destructive inflammatory immune response that occurs with advancing disease. Another justification cited for giving steroids is to treat suspected adrenal insufficiency in those with refractory shock. Of note, both practices are endorsed in the recent Surviving Sepsis Campaign guidelines on management of critically ill patients with COVID-19 (Intensive Care Med. 2020 May;46[5]:854-87).
But those recommendations – numbers 22 and 42 out of a total of 50 recommendations included in the guidelines – should never have been made, according to Dr. Pickkers, professor of experimental intensive care medicine at Radboud University Medical Center in Nijmegen, the Netherlands.
Dueling guidelines
The Surviving Sepsis Campaign guidelines, which were developed by a panel comprising 36 experts in 12 countries, are quite frank in conceding that the guidance in favor of corticosteroids are weak recommendations based on low-quality evidence.
The guidelines recommend against using corticosteroids to try to modulate the immune system in mechanically ventilated COVID-19 patients without acute respiratory distress syndrome (ARDS), but do recommend steroids in those with COVID-19 and ARDS. However, the guidelines also note that, because of the very low quality of the evidence, some experts on the panel preferred not to issue a pro-steroids recommendation at all until higher-quality evidence becomes available. Dr. Pickkers said he believes that the minority view should have prevailed. Moreover, current COVID-19 guidance from the World Health Organization is at odds with the Surviving Sepsis Campaign recommendations; the WHO advises against corticosteroids unless the treatment is indicated for a reason other than immunomodulation, he noted.
The evidence in favor of steroids in an effort to blunt the immune response in COVID patients with ARDS is based largely upon a single small, retrospective, non–peer-reviewed report that 5-7 days of treatment with 1-2 mg/kg per day of methylprednisolone was associated with shortened fever duration and need for supplemental oxygen.
The evidence against steroids for immunomodulation comes mainly from earlier studies of the SARS and MERS novel coronaviruses. For example, in a multicenter study of 309 patients with the MERS (Middle East respiratory syndrome) virus, those who received corticosteroids received no benefit and experienced delayed viral clearance (Am J Respir Crit Care Med. 2018 Mar 15;197[6]:757-67).
“The thing is, virtually all COVID-19 patients in the ICU fulfill the criteria for ARDS, so following the Surviving Sepsis Campaign guidelines would have far-reaching consequences,” Dr. Pickkers said.
Those consequences include a theoretic potential for serious harm arising from dampening the immune response at a point in the course of COVID-19 when the virus is still present, which could result in slowed viral clearance and prolonged viral shedding. Moreover so far no one has been able to identify a sweet spot in the disease course where the viral load has waned and the immune response is sufficiently early that intervention with corticosteroids might have an optimal benefit/risk ratio, he continued.
“My opinion is that at this moment there is no benefit at all for corticosteroids for immunomodulation in patients with COVID-19,” Dr. Pickkers said. “My personal recommendation, in contrast to the Surviving Sepsis Campaign recommendation, is not to use this therapy outside of a study.”
He added that randomized, controlled trials of corticosteroid therapy in critically ill patients with COVID-19 are ongoing in Europe and the United States, including the large RECOVERY study of dexamethasone in the United Kingdom.
As for the Surviving Sepsis Campaign recommendation to use corticosteroids to treat refractory shock in COVID-19, Dr. Pickkers dismissed this guidance as largely irrelevant. That’s because few patients with COVID-19 who need mechanical ventilation have refractory shock as evidenced by the need for a high infusion rate of norepinephrine. Anyway, he noted, that Surviving Sepsis recommendation is based upon extrapolation from evidence of benefit in bacterial septic shock patients, which he deemed to be of questionable relevance to the COVID-19 pandemic.
Attacking the fibroproliferative phase of ARDS
First off, Dr. Pickkers conceded, there is no evidence that treatment with corticosteroids to prevent lung fibrosis in COVID-19 patients with nonresolving ARDS is an effective strategy; the pandemic is simply too new at this point for the appropriate studies to have been done. But this much is known: Postmortem pathologic studies show fibroplastic proliferation is present in the lungs of COVID-19 patients, as in those who die of ARDS of other causes. Also, COVID-19 patients typically aren’t admitted to the ICU until day 11 or 12 after developing their first symptoms, so by the time they display indications that their ARDS is not resolving, the virus has typically left the scene; thus, there is little risk at that point that corticosteroids will promote viral proliferation. Additionally, studies in critically ill patients with nonresolving ARDS of other causes show clinically meaningful benefits for corticosteroid therapy.
Dr. Pickkers cited as “must reading” an analysis of five randomized trials of corticosteroid therapy in a total of 518 patients with acute lung injury ARDS of non–COVID-19 origin. The analysis by investigators at the University of Tennessee, Memphis, concluded that treatment resulted in clinically meaningful reductions in duration of mechanical ventilation and ICU length of stay. Moreover, in the 400 patients whose steroid therapy commenced before day 14 of ARDS, there was a statistically significant 22% reduction in risk of death, compared with patients in whom corticosteroids were started later (Intensive Care Med. 2008 Jan;34[1]:61-9).
Session cochair Jan De Waele, MD, PhD, struck a cautious note, remarking, “It’s my perception that we’re using the evidence that we’ve gathered in other conditions and are now trying to apply it in COVID-19. But quality data on patients with COVID-19 itself is pretty scare, and it’s really hard to say whether this disease behaves similarly to bacterial septic shock or to other viral infections.”
“We need more information about the use of corticosteroids in COVID-19, although I think a lot of people are using it at this moment,” added Dr. De Waele, a surgical intensivist at Ghent (Belgium) University.
That being said, he asked Dr. Pickkers when he considers using corticosteroids to prevent pulmonary fibrosis.
Dr. Pickkers said that when he notices that a COVID-19 patient’s lung compliance is worsening, that stiff lung is a clue that fibrosis is occurring and is having clinical consequences. “We also measure blood procollagen, a not very sensitive but moderately specific marker of fibroproliferation. If we see an increase in this biomarker and the lung mechanics are changing, then we do treat these patients with corticosteroids,” Dr. Pickkers replied.
He and his colleagues try to start steroids before day 14 of ARDS, and they continue treatment for longer than 7 days in order to prevent a rebound inflammatory response upon treatment discontinuation. They also avoid using neuromuscular agents and engage in meticulous infection surveillance in order to minimize potential complications of corticosteroid therapy in the ICU.
Dr. Pickkers reported having no financial conflicts regarding his presentation.
What is your diagnosis? - June 2020
Phlegmonous gastritis
The patient was treated with intravenous antibiotics (amoxicillin/clavulanic acid 6.6 g/d) and a proton pump inhibitor (esomeprazole 80 mg/d). Within a few days, her clinical status improved and abdominal ultrasound examination documented regression of the gastric wall thickening. Laboratory screening for predisposing factors such as diabetes mellitus, infection with human immunodeficiency virus, or immunoglobulin deficiency were negative and there was no clinical evidence of Crohn’s disease. Antibiotic treatment was stopped after 2 weeks. Six months later, follow-up gastroscopy was performed confirming complete resolution of the inflammatory changes in the stomach.
Phlegmonous gastritis is a rare but potentially life-threatening bacterial infection of the gastric wall. Since its first description in 1862, about 500 cases have been reported worldwide. Whereas the original reports dating back to the preantibiotic area suggest very high mortality rates in the range of 90%, phlegmonous gastritis still represents a life-threatening condition.1,2 In about one-half of the cases, acquired immunodeficiency states such as diabetes mellitus, human immunodeficiency virus, or alcoholism are identified as predisposing factors. In addition, gastric biopsies may herald the development of phlegmonous gastritis. Streptococcus spp. account for the majority of the cases, which can be isolated in about 70% of patients.1 Other organisms such as Staphylococcus spp., Escherichia coli Haemophilus influenzae, and Proteus or Clostridium spp. have been described as pathogens associated with this uncommon condition. Affected patients typically present with nonspecific symptoms such as abdominal pain, fever, nausea, vomitus, hematemesis, or diarrhea. In light of the devastating natural course of phlegmonous gastritis, timely preemptive administration of broad spectrum antibiotic along with a high index of suspicion are paramount. A computed tomography scan and transabdominal ultrasound examination are useful as initial tests, whereas endoscopic ultrasound examination typically demonstrates a diffusely thickened, hypoechogenic submucosal wall layer that is not commonly found in patients with other submucosal lesions, such as carcinoid or leiomyoma. The diagnosis can be confirmed by endoscopic forceps biopsy provided that sufficient submucosal tissue is included.1 Surgery should only be considered for cases refractory to conservative treatment.
References
1. Kim G, Ward J, Henessey B, et al. Phlegmonous gastritis: case report and review. Gastrointest Endosc. 2005;61:168-74.
2. Starr A, Wilson J. Phlegmonous gastritis. Ann Surg. 1957;145:88-93.
ginews@gastro.org
Phlegmonous gastritis
The patient was treated with intravenous antibiotics (amoxicillin/clavulanic acid 6.6 g/d) and a proton pump inhibitor (esomeprazole 80 mg/d). Within a few days, her clinical status improved and abdominal ultrasound examination documented regression of the gastric wall thickening. Laboratory screening for predisposing factors such as diabetes mellitus, infection with human immunodeficiency virus, or immunoglobulin deficiency were negative and there was no clinical evidence of Crohn’s disease. Antibiotic treatment was stopped after 2 weeks. Six months later, follow-up gastroscopy was performed confirming complete resolution of the inflammatory changes in the stomach.
Phlegmonous gastritis is a rare but potentially life-threatening bacterial infection of the gastric wall. Since its first description in 1862, about 500 cases have been reported worldwide. Whereas the original reports dating back to the preantibiotic area suggest very high mortality rates in the range of 90%, phlegmonous gastritis still represents a life-threatening condition.1,2 In about one-half of the cases, acquired immunodeficiency states such as diabetes mellitus, human immunodeficiency virus, or alcoholism are identified as predisposing factors. In addition, gastric biopsies may herald the development of phlegmonous gastritis. Streptococcus spp. account for the majority of the cases, which can be isolated in about 70% of patients.1 Other organisms such as Staphylococcus spp., Escherichia coli Haemophilus influenzae, and Proteus or Clostridium spp. have been described as pathogens associated with this uncommon condition. Affected patients typically present with nonspecific symptoms such as abdominal pain, fever, nausea, vomitus, hematemesis, or diarrhea. In light of the devastating natural course of phlegmonous gastritis, timely preemptive administration of broad spectrum antibiotic along with a high index of suspicion are paramount. A computed tomography scan and transabdominal ultrasound examination are useful as initial tests, whereas endoscopic ultrasound examination typically demonstrates a diffusely thickened, hypoechogenic submucosal wall layer that is not commonly found in patients with other submucosal lesions, such as carcinoid or leiomyoma. The diagnosis can be confirmed by endoscopic forceps biopsy provided that sufficient submucosal tissue is included.1 Surgery should only be considered for cases refractory to conservative treatment.
References
1. Kim G, Ward J, Henessey B, et al. Phlegmonous gastritis: case report and review. Gastrointest Endosc. 2005;61:168-74.
2. Starr A, Wilson J. Phlegmonous gastritis. Ann Surg. 1957;145:88-93.
ginews@gastro.org
Phlegmonous gastritis
The patient was treated with intravenous antibiotics (amoxicillin/clavulanic acid 6.6 g/d) and a proton pump inhibitor (esomeprazole 80 mg/d). Within a few days, her clinical status improved and abdominal ultrasound examination documented regression of the gastric wall thickening. Laboratory screening for predisposing factors such as diabetes mellitus, infection with human immunodeficiency virus, or immunoglobulin deficiency were negative and there was no clinical evidence of Crohn’s disease. Antibiotic treatment was stopped after 2 weeks. Six months later, follow-up gastroscopy was performed confirming complete resolution of the inflammatory changes in the stomach.
Phlegmonous gastritis is a rare but potentially life-threatening bacterial infection of the gastric wall. Since its first description in 1862, about 500 cases have been reported worldwide. Whereas the original reports dating back to the preantibiotic area suggest very high mortality rates in the range of 90%, phlegmonous gastritis still represents a life-threatening condition.1,2 In about one-half of the cases, acquired immunodeficiency states such as diabetes mellitus, human immunodeficiency virus, or alcoholism are identified as predisposing factors. In addition, gastric biopsies may herald the development of phlegmonous gastritis. Streptococcus spp. account for the majority of the cases, which can be isolated in about 70% of patients.1 Other organisms such as Staphylococcus spp., Escherichia coli Haemophilus influenzae, and Proteus or Clostridium spp. have been described as pathogens associated with this uncommon condition. Affected patients typically present with nonspecific symptoms such as abdominal pain, fever, nausea, vomitus, hematemesis, or diarrhea. In light of the devastating natural course of phlegmonous gastritis, timely preemptive administration of broad spectrum antibiotic along with a high index of suspicion are paramount. A computed tomography scan and transabdominal ultrasound examination are useful as initial tests, whereas endoscopic ultrasound examination typically demonstrates a diffusely thickened, hypoechogenic submucosal wall layer that is not commonly found in patients with other submucosal lesions, such as carcinoid or leiomyoma. The diagnosis can be confirmed by endoscopic forceps biopsy provided that sufficient submucosal tissue is included.1 Surgery should only be considered for cases refractory to conservative treatment.
References
1. Kim G, Ward J, Henessey B, et al. Phlegmonous gastritis: case report and review. Gastrointest Endosc. 2005;61:168-74.
2. Starr A, Wilson J. Phlegmonous gastritis. Ann Surg. 1957;145:88-93.
ginews@gastro.org
A previously healthy 41-year-old woman presented with upper abdominal pain, nausea, vomiting, and fever for 4 days. On admission, the patient was febrile (40.1°C); her blood pressure, heart rate, and peripheral oxygen saturation were normal. Laboratory findings were notable for a C-reactive protein of 190 mg/L (reference range, less than 5 mg/L) along with a white cell count of 21,600/mm3 (reference range, 4,500-10,500/mm3). Liver enzymes, pancreatic lipase, and bilirubin were within normal limits. A computed tomography scan of the abdomen revealed wall thickening of the gastric antrum (Figure A).
Gastroscopy showed a heavily distorted gastric antrum with a fistula (Figure B, C). Consecutively, endoscopic ultrasound examination was performed, confirming circumferential thickening of the antral wall up to 20 mm with inhomogeneous hypoechogenic areas within the submucosa (Figure D). Deep endoscopic forceps biopsies were obtained. Histopathologic examination revealed extensive infiltration of the mucosa and submucosa by neutrophils (Figure E, F) and microbial cultures were positive for Streptococcus spp. (S. pyogenes, viridans group streptococci) and Rothia mucilaginosa.