A single, baseline prostate-specific antigen (PSA) level measured at midlife predicted risk of lethal prostate cancer over a 30-year follow-up, according to a nested, case-control study among men who participated in the Physicians’ Health Study.

PSA levels at the 90th percentile and above, compared with levels at the median and lower, were associated with increased risk of lethal prostate cancer (PCa) across all age groups: for men aged 40-49 years, the odds ratio was 8.7 (95% confidence interval, 1.0-78.2), for 50-54 years, 12.6 (1.4-110.4), and for 55-59 years, 6.9 (2.5-19.1). PSA levels above the median were associated with increased risk of all PCa: odds ratios were 7.3 (95% CI, 2.4-21.8) for 40-49 years, 7.6 (3.4-17.2) for 50-54 years, and 10.1 (5.2-19.6) for 55-59 years.

“These data identify subgroups of men, on the basis of their PSA levels at a given age, with widely divergent lifetime risk of PCa death, who therefore could benefit from screening intervals tailored to their actual magnitude of risk,” wrote Dr. Mark Preston of Brigham and Women’s Hospital, Boston, and colleagues (J Clin Oncol. 2016 Jun 13. doi: 10.1200/JCO.2016.66.7527).

The investigators noted that one of seven men with PSA greater than 2.1 mg/mL at 55-59 years and one of 12 men with PSA greater than 2.1 ng/mL at 50-54 years died as a result of PCa within 30 years.

“These findings do not necessarily imply that prostate biopsy or definitive treatment is immediately required in younger men with higher PSA levels at baseline, because this could lead to overdiagnosis, but only that they undergo more intensive PSA screening to enable earlier identification of cancer and potential cure while still possible,” the investigators wrote.

As a subset of the Physicians’ Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene, 14,916 men aged 40-84 years provided a blood sample during 1982-1984. Total PSA was determined from stored specimens, and self-reported incident PCa cases from 1982 to 2012 were confirmed through medical records.

In answer to the question of whether a low PSA level at 40-49 years might safely exempt men from further screening, results showed that for PSA levels below the 25th percentile, cumulative incidence of lethal PCa at 30 years was 0.37% (0.05-1.70) for men 40-44 years and 0.97% (0.30-2.49) for men 45-49 years. Because a small risk remains even with an exceptionally low first measure, another PSA test during the lifetime of men 40-49 is prudent, according to the researchers. At age 60 years, men with PSA below the median are unlikely to develop lethal PCa, based on the analysis.

[email protected]

A single, baseline prostate-specific antigen (PSA) level measured at midlife predicted risk of lethal prostate cancer over a 30-year follow-up, according to a nested, case-control study among men who participated in the Physicians’ Health Study.

PSA levels at the 90th percentile and above, compared with levels at the median and lower, were associated with increased risk of lethal prostate cancer (PCa) across all age groups: for men aged 40-49 years, the odds ratio was 8.7 (95% confidence interval, 1.0-78.2), for 50-54 years, 12.6 (1.4-110.4), and for 55-59 years, 6.9 (2.5-19.1). PSA levels above the median were associated with increased risk of all PCa: odds ratios were 7.3 (95% CI, 2.4-21.8) for 40-49 years, 7.6 (3.4-17.2) for 50-54 years, and 10.1 (5.2-19.6) for 55-59 years.

“These data identify subgroups of men, on the basis of their PSA levels at a given age, with widely divergent lifetime risk of PCa death, who therefore could benefit from screening intervals tailored to their actual magnitude of risk,” wrote Dr. Mark Preston of Brigham and Women’s Hospital, Boston, and colleagues (J Clin Oncol. 2016 Jun 13. doi: 10.1200/JCO.2016.66.7527).

The investigators noted that one of seven men with PSA greater than 2.1 mg/mL at 55-59 years and one of 12 men with PSA greater than 2.1 ng/mL at 50-54 years died as a result of PCa within 30 years.

“These findings do not necessarily imply that prostate biopsy or definitive treatment is immediately required in younger men with higher PSA levels at baseline, because this could lead to overdiagnosis, but only that they undergo more intensive PSA screening to enable earlier identification of cancer and potential cure while still possible,” the investigators wrote.

As a subset of the Physicians’ Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene, 14,916 men aged 40-84 years provided a blood sample during 1982-1984. Total PSA was determined from stored specimens, and self-reported incident PCa cases from 1982 to 2012 were confirmed through medical records.

In answer to the question of whether a low PSA level at 40-49 years might safely exempt men from further screening, results showed that for PSA levels below the 25th percentile, cumulative incidence of lethal PCa at 30 years was 0.37% (0.05-1.70) for men 40-44 years and 0.97% (0.30-2.49) for men 45-49 years. Because a small risk remains even with an exceptionally low first measure, another PSA test during the lifetime of men 40-49 is prudent, according to the researchers. At age 60 years, men with PSA below the median are unlikely to develop lethal PCa, based on the analysis.

[email protected]

A single, baseline prostate-specific antigen (PSA) level measured at midlife predicted risk of lethal prostate cancer over a 30-year follow-up, according to a nested, case-control study among men who participated in the Physicians’ Health Study.

PSA levels at the 90th percentile and above, compared with levels at the median and lower, were associated with increased risk of lethal prostate cancer (PCa) across all age groups: for men aged 40-49 years, the odds ratio was 8.7 (95% confidence interval, 1.0-78.2), for 50-54 years, 12.6 (1.4-110.4), and for 55-59 years, 6.9 (2.5-19.1). PSA levels above the median were associated with increased risk of all PCa: odds ratios were 7.3 (95% CI, 2.4-21.8) for 40-49 years, 7.6 (3.4-17.2) for 50-54 years, and 10.1 (5.2-19.6) for 55-59 years.

“These data identify subgroups of men, on the basis of their PSA levels at a given age, with widely divergent lifetime risk of PCa death, who therefore could benefit from screening intervals tailored to their actual magnitude of risk,” wrote Dr. Mark Preston of Brigham and Women’s Hospital, Boston, and colleagues (J Clin Oncol. 2016 Jun 13. doi: 10.1200/JCO.2016.66.7527).

The investigators noted that one of seven men with PSA greater than 2.1 mg/mL at 55-59 years and one of 12 men with PSA greater than 2.1 ng/mL at 50-54 years died as a result of PCa within 30 years.

“These findings do not necessarily imply that prostate biopsy or definitive treatment is immediately required in younger men with higher PSA levels at baseline, because this could lead to overdiagnosis, but only that they undergo more intensive PSA screening to enable earlier identification of cancer and potential cure while still possible,” the investigators wrote.

As a subset of the Physicians’ Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene, 14,916 men aged 40-84 years provided a blood sample during 1982-1984. Total PSA was determined from stored specimens, and self-reported incident PCa cases from 1982 to 2012 were confirmed through medical records.

In answer to the question of whether a low PSA level at 40-49 years might safely exempt men from further screening, results showed that for PSA levels below the 25th percentile, cumulative incidence of lethal PCa at 30 years was 0.37% (0.05-1.70) for men 40-44 years and 0.97% (0.30-2.49) for men 45-49 years. Because a small risk remains even with an exceptionally low first measure, another PSA test during the lifetime of men 40-49 is prudent, according to the researchers. At age 60 years, men with PSA below the median are unlikely to develop lethal PCa, based on the analysis.

[email protected]

CHICAGO – The immune checkpoint inhibitor atezolizumab is efficacious when used as first-line therapy for advanced urothelial carcinoma, according to a study reported at the annual meeting of the American Society of Clinical Oncology.

The study – cohort 1 of the IMvigor210 trial – was conducted among 119 cisplatin-ineligible patients with metastatic or locally advanced disease. All were treated with the antibody atezolizumab, which targets PD-L1 (programmed death–ligand 1), a negative regulator of the immune system, and thereby promotes the antitumor immune response.

Nearly a quarter of patients had a tumor response to atezolizumab, and median overall survival approached 15 months, first author Dr. Arjun V. Balar of the New York University Langone Medical Center and director of genitourinary medical oncology at the NYU Perlmutter Cancer Center, New York, reported in a session and press briefing.

“Overall, this therapy was efficacious and also very well tolerated,” he commented. “These data make a compelling argument for atezolizumab to be a potential new standard of care in patients with cisplatin-ineligible metastatic urothelial cancer. However, moreover, they could represent the beginning of a seismic shift in our treatment approach to all patients with metastatic disease, irrespective of their eligibility for cisplatin.”

Positive findings from the trial’s cohort 2, patients who had already received platinum-based chemotherapy for advanced disease, recently led to the agent’s approval by the Food and Drug Administration for use in that population.

Cohort 1 was initially set up as an exploratory study but was expanded, Dr. Balar explained. “I do think that there is a benefit there, but until we have comparative data, it’s going to be really hard to hold that against immunotherapy necessarily,” he acknowledged. “That being said, do I envision a future where there is PD-L1 and PD-1 targeted therapy as a front-line therapy? Yes, absolutely, I think we are headed in that direction. We just need the trials to show it.”

ASCO expert Dr. Charles Ryan, professor of clinical medicine and urology program leader, genitourinary medical oncology, at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, concurred, saying, “I think it is safe at this point to envision a future where PD-L1 therapy could be used in the front line, but we do need to do those confirmatory studies.

“I would just underscore that in this study, the importance is that this is cisplatin ineligible as opposed to carboplatin treated,” Dr. Ryan added. “Cisplatin is the only platinum in bladder cancer that is associated with a survival benefit, so this is a very significant point to make. A very substantial part of the bladder cancer population, many patients out there, are cisplatin ineligible due to a variety of reasons, because organ dysfunction is quite common in advanced urothelial cancer.”

Patients were entered into IMVigor210’s cohort 1 if they had impaired kidney function, peripheral neuropathy, moderate to severe hearing loss, or poor performance status, precluding the use of cisplatin.

All were treated with atezolizumab (Tecentriq) every 3 weeks until investigator-defined progression. To evaluate a potential biomarker for benefit, the investigators assessed PD-L1 expression on tumor-infiltrating immune cells by immunohistochemistry in archival tissue.

Study results showed that with a median follow-up of 14.4 months, the centrally confirmed overall response rate, the study’s primary endpoint, was 24% (7% of patients had a complete response and 17% had a partial response), Dr. Balar reported.

Complete responses were seen in all subgroups of patients stratified by PD-L1 expression. Fully 75% of all responses were still ongoing at the time of data cutoff, and the median duration of response has not yet been reached in any of the subgroups.

The median duration of overall survival was 14.8 months, and the 1-year rate of overall survival was 57%, although data for that endpoint are still immature. Survival also appeared to be similar regardless of PD-L1 expression.

Taken together, these efficacy findings compare favorably with those seen historically in similar patients treated with other agents in trials and in real-world settings, according to Dr. Balar.

Atezolizumab was well tolerated, with only 6% of patients experiencing an adverse event leading to trial discontinuation. Most events seen were of grade 1 or 2 severity; a single patient had a grade 5 event (sepsis).

About 15% of patients had treatment-related grade 3 or 4 adverse events, about the same as the rate seen in cohort 2. The most common were fatigue and an increase in liver enzymes.

Overall, 14% of patients had an immune-mediated adverse event requiring corticosteroid treatment. “Notably, no patients required any other immunosuppression beyond steroids for the management of an immune-related adverse event,” he reported

The PD-L1 analyses in the trial had some limitations, Dr. Balar said. “PD-L1 testing continues to be the most hotly contested issue,” he said. “Obviously, the immune system is very dynamic, and we were testing something in archival specimens, in a static environment, so there are obviously all the caveats there.”

Some data have suggested that mutational burden may help identify the patient subset who will benefit. However, “to be able to make your decision in the clinic, those types of readouts need to be timely …, and I think that’s the gap,” he commented. “So in the future, is the right biomarker PD-1 or PD-L1? My hunch is no, that is probably not the right biomarker, there are probably better ones, and those are being worked on.”

Dr. Balar disclosed that he has a consulting or advisory role with Cerulean Pharma, Dendreon, Pfizer, and Roche/Genentech. The trial was sponsored by Hoffmann-La Roche. Ventana Medical Systems assisted with PD-L1 testing.

CHICAGO – The immune checkpoint inhibitor atezolizumab is efficacious when used as first-line therapy for advanced urothelial carcinoma, according to a study reported at the annual meeting of the American Society of Clinical Oncology.

The study – cohort 1 of the IMvigor210 trial – was conducted among 119 cisplatin-ineligible patients with metastatic or locally advanced disease. All were treated with the antibody atezolizumab, which targets PD-L1 (programmed death–ligand 1), a negative regulator of the immune system, and thereby promotes the antitumor immune response.

Nearly a quarter of patients had a tumor response to atezolizumab, and median overall survival approached 15 months, first author Dr. Arjun V. Balar of the New York University Langone Medical Center and director of genitourinary medical oncology at the NYU Perlmutter Cancer Center, New York, reported in a session and press briefing.

“Overall, this therapy was efficacious and also very well tolerated,” he commented. “These data make a compelling argument for atezolizumab to be a potential new standard of care in patients with cisplatin-ineligible metastatic urothelial cancer. However, moreover, they could represent the beginning of a seismic shift in our treatment approach to all patients with metastatic disease, irrespective of their eligibility for cisplatin.”

Positive findings from the trial’s cohort 2, patients who had already received platinum-based chemotherapy for advanced disease, recently led to the agent’s approval by the Food and Drug Administration for use in that population.

Cohort 1 was initially set up as an exploratory study but was expanded, Dr. Balar explained. “I do think that there is a benefit there, but until we have comparative data, it’s going to be really hard to hold that against immunotherapy necessarily,” he acknowledged. “That being said, do I envision a future where there is PD-L1 and PD-1 targeted therapy as a front-line therapy? Yes, absolutely, I think we are headed in that direction. We just need the trials to show it.”

ASCO expert Dr. Charles Ryan, professor of clinical medicine and urology program leader, genitourinary medical oncology, at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, concurred, saying, “I think it is safe at this point to envision a future where PD-L1 therapy could be used in the front line, but we do need to do those confirmatory studies.

“I would just underscore that in this study, the importance is that this is cisplatin ineligible as opposed to carboplatin treated,” Dr. Ryan added. “Cisplatin is the only platinum in bladder cancer that is associated with a survival benefit, so this is a very significant point to make. A very substantial part of the bladder cancer population, many patients out there, are cisplatin ineligible due to a variety of reasons, because organ dysfunction is quite common in advanced urothelial cancer.”

Patients were entered into IMVigor210’s cohort 1 if they had impaired kidney function, peripheral neuropathy, moderate to severe hearing loss, or poor performance status, precluding the use of cisplatin.

All were treated with atezolizumab (Tecentriq) every 3 weeks until investigator-defined progression. To evaluate a potential biomarker for benefit, the investigators assessed PD-L1 expression on tumor-infiltrating immune cells by immunohistochemistry in archival tissue.

Study results showed that with a median follow-up of 14.4 months, the centrally confirmed overall response rate, the study’s primary endpoint, was 24% (7% of patients had a complete response and 17% had a partial response), Dr. Balar reported.

Complete responses were seen in all subgroups of patients stratified by PD-L1 expression. Fully 75% of all responses were still ongoing at the time of data cutoff, and the median duration of response has not yet been reached in any of the subgroups.

The median duration of overall survival was 14.8 months, and the 1-year rate of overall survival was 57%, although data for that endpoint are still immature. Survival also appeared to be similar regardless of PD-L1 expression.

Taken together, these efficacy findings compare favorably with those seen historically in similar patients treated with other agents in trials and in real-world settings, according to Dr. Balar.

Atezolizumab was well tolerated, with only 6% of patients experiencing an adverse event leading to trial discontinuation. Most events seen were of grade 1 or 2 severity; a single patient had a grade 5 event (sepsis).

About 15% of patients had treatment-related grade 3 or 4 adverse events, about the same as the rate seen in cohort 2. The most common were fatigue and an increase in liver enzymes.

Overall, 14% of patients had an immune-mediated adverse event requiring corticosteroid treatment. “Notably, no patients required any other immunosuppression beyond steroids for the management of an immune-related adverse event,” he reported

The PD-L1 analyses in the trial had some limitations, Dr. Balar said. “PD-L1 testing continues to be the most hotly contested issue,” he said. “Obviously, the immune system is very dynamic, and we were testing something in archival specimens, in a static environment, so there are obviously all the caveats there.”

Some data have suggested that mutational burden may help identify the patient subset who will benefit. However, “to be able to make your decision in the clinic, those types of readouts need to be timely …, and I think that’s the gap,” he commented. “So in the future, is the right biomarker PD-1 or PD-L1? My hunch is no, that is probably not the right biomarker, there are probably better ones, and those are being worked on.”

Dr. Balar disclosed that he has a consulting or advisory role with Cerulean Pharma, Dendreon, Pfizer, and Roche/Genentech. The trial was sponsored by Hoffmann-La Roche. Ventana Medical Systems assisted with PD-L1 testing.

CHICAGO – The immune checkpoint inhibitor atezolizumab is efficacious when used as first-line therapy for advanced urothelial carcinoma, according to a study reported at the annual meeting of the American Society of Clinical Oncology.

The study – cohort 1 of the IMvigor210 trial – was conducted among 119 cisplatin-ineligible patients with metastatic or locally advanced disease. All were treated with the antibody atezolizumab, which targets PD-L1 (programmed death–ligand 1), a negative regulator of the immune system, and thereby promotes the antitumor immune response.

Nearly a quarter of patients had a tumor response to atezolizumab, and median overall survival approached 15 months, first author Dr. Arjun V. Balar of the New York University Langone Medical Center and director of genitourinary medical oncology at the NYU Perlmutter Cancer Center, New York, reported in a session and press briefing.

“Overall, this therapy was efficacious and also very well tolerated,” he commented. “These data make a compelling argument for atezolizumab to be a potential new standard of care in patients with cisplatin-ineligible metastatic urothelial cancer. However, moreover, they could represent the beginning of a seismic shift in our treatment approach to all patients with metastatic disease, irrespective of their eligibility for cisplatin.”

Positive findings from the trial’s cohort 2, patients who had already received platinum-based chemotherapy for advanced disease, recently led to the agent’s approval by the Food and Drug Administration for use in that population.

Cohort 1 was initially set up as an exploratory study but was expanded, Dr. Balar explained. “I do think that there is a benefit there, but until we have comparative data, it’s going to be really hard to hold that against immunotherapy necessarily,” he acknowledged. “That being said, do I envision a future where there is PD-L1 and PD-1 targeted therapy as a front-line therapy? Yes, absolutely, I think we are headed in that direction. We just need the trials to show it.”

ASCO expert Dr. Charles Ryan, professor of clinical medicine and urology program leader, genitourinary medical oncology, at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, concurred, saying, “I think it is safe at this point to envision a future where PD-L1 therapy could be used in the front line, but we do need to do those confirmatory studies.

“I would just underscore that in this study, the importance is that this is cisplatin ineligible as opposed to carboplatin treated,” Dr. Ryan added. “Cisplatin is the only platinum in bladder cancer that is associated with a survival benefit, so this is a very significant point to make. A very substantial part of the bladder cancer population, many patients out there, are cisplatin ineligible due to a variety of reasons, because organ dysfunction is quite common in advanced urothelial cancer.”

Patients were entered into IMVigor210’s cohort 1 if they had impaired kidney function, peripheral neuropathy, moderate to severe hearing loss, or poor performance status, precluding the use of cisplatin.

All were treated with atezolizumab (Tecentriq) every 3 weeks until investigator-defined progression. To evaluate a potential biomarker for benefit, the investigators assessed PD-L1 expression on tumor-infiltrating immune cells by immunohistochemistry in archival tissue.

Study results showed that with a median follow-up of 14.4 months, the centrally confirmed overall response rate, the study’s primary endpoint, was 24% (7% of patients had a complete response and 17% had a partial response), Dr. Balar reported.

Complete responses were seen in all subgroups of patients stratified by PD-L1 expression. Fully 75% of all responses were still ongoing at the time of data cutoff, and the median duration of response has not yet been reached in any of the subgroups.

The median duration of overall survival was 14.8 months, and the 1-year rate of overall survival was 57%, although data for that endpoint are still immature. Survival also appeared to be similar regardless of PD-L1 expression.

Taken together, these efficacy findings compare favorably with those seen historically in similar patients treated with other agents in trials and in real-world settings, according to Dr. Balar.

Atezolizumab was well tolerated, with only 6% of patients experiencing an adverse event leading to trial discontinuation. Most events seen were of grade 1 or 2 severity; a single patient had a grade 5 event (sepsis).

About 15% of patients had treatment-related grade 3 or 4 adverse events, about the same as the rate seen in cohort 2. The most common were fatigue and an increase in liver enzymes.

Overall, 14% of patients had an immune-mediated adverse event requiring corticosteroid treatment. “Notably, no patients required any other immunosuppression beyond steroids for the management of an immune-related adverse event,” he reported

The PD-L1 analyses in the trial had some limitations, Dr. Balar said. “PD-L1 testing continues to be the most hotly contested issue,” he said. “Obviously, the immune system is very dynamic, and we were testing something in archival specimens, in a static environment, so there are obviously all the caveats there.”

Some data have suggested that mutational burden may help identify the patient subset who will benefit. However, “to be able to make your decision in the clinic, those types of readouts need to be timely …, and I think that’s the gap,” he commented. “So in the future, is the right biomarker PD-1 or PD-L1? My hunch is no, that is probably not the right biomarker, there are probably better ones, and those are being worked on.”

Dr. Balar disclosed that he has a consulting or advisory role with Cerulean Pharma, Dendreon, Pfizer, and Roche/Genentech. The trial was sponsored by Hoffmann-La Roche. Ventana Medical Systems assisted with PD-L1 testing.

LOS ANGELES – In the clinical experience of Dr. Ian C. Lavery, prevention efforts are the best defense against local recurrence of rectal cancer.

“This means adjuvant treatment, if necessary, neoadjuvant treatment, and a meticulous surgical operation,” Dr. Lavery of the department of colorectal surgery at the Cleveland Clinic said at the annual meeting of the American Society of Colon and Rectal Surgeons. “If the circumferential resection margin is negative, the local recurrence rate is 10% or less. If it’s positive, local recurrence goes up to 78%. Even when we attempt to do the perfect total mesorectal excision, local recurrence is in the order of 4%.”

Selective use of radiotherapy in the neoadjuvant setting appears to be reducing the incidence of local recurrence, “certainly in the short term,” he added. “In the long term, I’m not sure we know the true answer to that yet. Using other techniques like washing the rectal stump out, the use of stapling, and en-bloc resection if necessary [can help prevention efforts].”

The incidence of local rectal cancer recurrence is reported to be between 3% and 50%, but neither curative nor palliative treatment is standardized. “When you get local recurrence after a rectal cancer operation, it’s a disaster,” Dr. Lavery said. “It may cause intractable pain, bleeding, perforation, obstruction, and sepsis – all incredibly difficult things to manage.”

Patients who develop a local recurrence of rectal cancer are often asymptomatic. A digital rectal exam (DRE) may or may not identify a recurrence and carcinoembryonic antigen levels are helpful on some occasions. According to Dr. Lavery, optimal surveillance consists of a clinical examination including DRE, endoscopy, blood tests, CT scans, MRI, and PET scans. “If they were all to be done routinely it would increase the detection earlier rather than later,” he said.

CT and MRI appear to be about 85% accurate but both modalities are “very poor at detecting peritoneal disease,” he said. PET scans for recurrent carcinoma have been shown to change the management in 20%-56% of cases (Ann Surg Oncol. 1997 Dec; 4:613-20).

While follow-up of patients who have undergone surgery for local rectal cancer is generally favored, there is no consensus on what the ideal follow-up timeline should be. “In my opinion, the more intensive follow-up is going to be better than the cursory conventional follow-up examination,” Dr. Lavery said. “One of the big reasons for that is the vast majority of recurrences are extraluminal so they may be difficult to feel. Doing endoscopy, you can’t see them if they’re extraluminal.”

The goal in treating recurrent rectal cancer is to improve quality of life, he continued, as the common symptoms include obstruction, pain, bleeding, bowel discharge, or perforation/abscess. Optimal treatment involves striving for tumor-free margins after the operation. “This may require en bloc resection of an adjacent prostate, bladder, lateral pelvic wall,” he said. “But clinically and radiologically, it’s very difficult to identify those patients that have a potentially R0 resection.”

Curative treatment is possible if the recurrence is locally resectable and the patient has minimal comorbidities. “The potential morbidity after the surgery has to be acceptable, considering the severity of the problem that we’re dealing with,” Dr. Lavery noted. “Distant disease also complicates the issue.”

Reasons to avoid resection include rigid tumor fixation, leg lymphedema, major vessel encasement, bilateral ureteric involvement, extensive para-aortic lymph node involvement, and radicular pain. “If you embark on one of these cases, you want to make it at least the first if not the only case of the day,” Dr. Lavery advised. “Anticipate the need for assistance during the operation, but above all, make sure you have optimal exposure to do the surgery.” He reported having no financial disclosures.

[email protected]

LOS ANGELES – In the clinical experience of Dr. Ian C. Lavery, prevention efforts are the best defense against local recurrence of rectal cancer.

“This means adjuvant treatment, if necessary, neoadjuvant treatment, and a meticulous surgical operation,” Dr. Lavery of the department of colorectal surgery at the Cleveland Clinic said at the annual meeting of the American Society of Colon and Rectal Surgeons. “If the circumferential resection margin is negative, the local recurrence rate is 10% or less. If it’s positive, local recurrence goes up to 78%. Even when we attempt to do the perfect total mesorectal excision, local recurrence is in the order of 4%.”

Selective use of radiotherapy in the neoadjuvant setting appears to be reducing the incidence of local recurrence, “certainly in the short term,” he added. “In the long term, I’m not sure we know the true answer to that yet. Using other techniques like washing the rectal stump out, the use of stapling, and en-bloc resection if necessary [can help prevention efforts].”

The incidence of local rectal cancer recurrence is reported to be between 3% and 50%, but neither curative nor palliative treatment is standardized. “When you get local recurrence after a rectal cancer operation, it’s a disaster,” Dr. Lavery said. “It may cause intractable pain, bleeding, perforation, obstruction, and sepsis – all incredibly difficult things to manage.”

Patients who develop a local recurrence of rectal cancer are often asymptomatic. A digital rectal exam (DRE) may or may not identify a recurrence and carcinoembryonic antigen levels are helpful on some occasions. According to Dr. Lavery, optimal surveillance consists of a clinical examination including DRE, endoscopy, blood tests, CT scans, MRI, and PET scans. “If they were all to be done routinely it would increase the detection earlier rather than later,” he said.

CT and MRI appear to be about 85% accurate but both modalities are “very poor at detecting peritoneal disease,” he said. PET scans for recurrent carcinoma have been shown to change the management in 20%-56% of cases (Ann Surg Oncol. 1997 Dec; 4:613-20).

While follow-up of patients who have undergone surgery for local rectal cancer is generally favored, there is no consensus on what the ideal follow-up timeline should be. “In my opinion, the more intensive follow-up is going to be better than the cursory conventional follow-up examination,” Dr. Lavery said. “One of the big reasons for that is the vast majority of recurrences are extraluminal so they may be difficult to feel. Doing endoscopy, you can’t see them if they’re extraluminal.”

The goal in treating recurrent rectal cancer is to improve quality of life, he continued, as the common symptoms include obstruction, pain, bleeding, bowel discharge, or perforation/abscess. Optimal treatment involves striving for tumor-free margins after the operation. “This may require en bloc resection of an adjacent prostate, bladder, lateral pelvic wall,” he said. “But clinically and radiologically, it’s very difficult to identify those patients that have a potentially R0 resection.”

Curative treatment is possible if the recurrence is locally resectable and the patient has minimal comorbidities. “The potential morbidity after the surgery has to be acceptable, considering the severity of the problem that we’re dealing with,” Dr. Lavery noted. “Distant disease also complicates the issue.”

Reasons to avoid resection include rigid tumor fixation, leg lymphedema, major vessel encasement, bilateral ureteric involvement, extensive para-aortic lymph node involvement, and radicular pain. “If you embark on one of these cases, you want to make it at least the first if not the only case of the day,” Dr. Lavery advised. “Anticipate the need for assistance during the operation, but above all, make sure you have optimal exposure to do the surgery.” He reported having no financial disclosures.

[email protected]

LOS ANGELES – In the clinical experience of Dr. Ian C. Lavery, prevention efforts are the best defense against local recurrence of rectal cancer.

“This means adjuvant treatment, if necessary, neoadjuvant treatment, and a meticulous surgical operation,” Dr. Lavery of the department of colorectal surgery at the Cleveland Clinic said at the annual meeting of the American Society of Colon and Rectal Surgeons. “If the circumferential resection margin is negative, the local recurrence rate is 10% or less. If it’s positive, local recurrence goes up to 78%. Even when we attempt to do the perfect total mesorectal excision, local recurrence is in the order of 4%.”

Selective use of radiotherapy in the neoadjuvant setting appears to be reducing the incidence of local recurrence, “certainly in the short term,” he added. “In the long term, I’m not sure we know the true answer to that yet. Using other techniques like washing the rectal stump out, the use of stapling, and en-bloc resection if necessary [can help prevention efforts].”

The incidence of local rectal cancer recurrence is reported to be between 3% and 50%, but neither curative nor palliative treatment is standardized. “When you get local recurrence after a rectal cancer operation, it’s a disaster,” Dr. Lavery said. “It may cause intractable pain, bleeding, perforation, obstruction, and sepsis – all incredibly difficult things to manage.”

Patients who develop a local recurrence of rectal cancer are often asymptomatic. A digital rectal exam (DRE) may or may not identify a recurrence and carcinoembryonic antigen levels are helpful on some occasions. According to Dr. Lavery, optimal surveillance consists of a clinical examination including DRE, endoscopy, blood tests, CT scans, MRI, and PET scans. “If they were all to be done routinely it would increase the detection earlier rather than later,” he said.

CT and MRI appear to be about 85% accurate but both modalities are “very poor at detecting peritoneal disease,” he said. PET scans for recurrent carcinoma have been shown to change the management in 20%-56% of cases (Ann Surg Oncol. 1997 Dec; 4:613-20).

While follow-up of patients who have undergone surgery for local rectal cancer is generally favored, there is no consensus on what the ideal follow-up timeline should be. “In my opinion, the more intensive follow-up is going to be better than the cursory conventional follow-up examination,” Dr. Lavery said. “One of the big reasons for that is the vast majority of recurrences are extraluminal so they may be difficult to feel. Doing endoscopy, you can’t see them if they’re extraluminal.”

The goal in treating recurrent rectal cancer is to improve quality of life, he continued, as the common symptoms include obstruction, pain, bleeding, bowel discharge, or perforation/abscess. Optimal treatment involves striving for tumor-free margins after the operation. “This may require en bloc resection of an adjacent prostate, bladder, lateral pelvic wall,” he said. “But clinically and radiologically, it’s very difficult to identify those patients that have a potentially R0 resection.”

Curative treatment is possible if the recurrence is locally resectable and the patient has minimal comorbidities. “The potential morbidity after the surgery has to be acceptable, considering the severity of the problem that we’re dealing with,” Dr. Lavery noted. “Distant disease also complicates the issue.”

Reasons to avoid resection include rigid tumor fixation, leg lymphedema, major vessel encasement, bilateral ureteric involvement, extensive para-aortic lymph node involvement, and radicular pain. “If you embark on one of these cases, you want to make it at least the first if not the only case of the day,” Dr. Lavery advised. “Anticipate the need for assistance during the operation, but above all, make sure you have optimal exposure to do the surgery.” He reported having no financial disclosures.

[email protected]

Applying the more stringent SPRINT criteria to a general population of persons with hypertension would yield a significant reduction in the number of people meeting their treatment goals, although those who do would achieve a significant reduction in their risk of cardiovascular disease, a study published June 13 in the Journal of the American College of Cardiology has found.

Min Jung Ko, Ph.D., of the National Evidence-Based Healthcare Collaborating Agency in Seoul, Korea, and coauthors explored the relative impacts of SPRINT target of less than 120 mm Hg for hypertension treatments with the 2014 hypertension recommendations of the Eighth Joint National Committee of less than 140 mm Hg, using data from 13,346 individuals in the Korean National Health and Nutrition Examination Survey of 2008-2013, and 67,965 individuals in the Korean National Health Insurance Service health examinee cohort of 2007.

©Ingram Publishing/thinkstockphotos.com

The investigators found that 11.9% of adults with hypertension would meet the treatment goals of the SPRINT criteria, compared with 70.8% who would meet the 2014 recommendations.

However, the analysis showed that those who met the more aggressive SPRINT treatment goal of systolic BP below 120 mm Hg also had the lowest 10-year risk of a major cardiovascular event (6.2%), compared with 7.7% in those who met the 2014 targets but not the SPRINT targets, and 9.4% in those who failed to meet the 2014 treatment targets (J Am Coll Cardiol. 2016 Jun 13. doi 10.1016/j.jacc.2016.03.572).

After adjustment for factors such as age, diabetes, chronic kidney disease, hyperlipidemia, body mass index, and smoking, the least-controlled group showed a 62% increase in the risk of cardiovascular events, compared with the SPRINT criteria group. Those who met the 2014 criteria had a 17% greater risk than those who met the SPRINT criteria.

“Despite greater cardiovascular protection with intensive BP lowering, achieving SPRINT-defined BP goals might not be easy or practical because the target BP was not met in more than one-half of the participants in the intensive-treatment group,” the authors wrote.

Individuals who were older, female, or had diabetes, chronic kidney disease, or prevalent cardiovascular disease were more likely to meet the stricter goals of SPRINT (Systolic Blood Pressure Intervention Trial), in which combined cardiovascular events occurred in 5.2% of patients treated to a target systolic blood pressure of less than 120 mm Hg and 6.8% of patients treated to a target of less than 140 mm Hg (N Engl J Med. 2015;373:2103-16).

Researchers also noted a significant linear association between lesser blood pressure control and an increased risk of myocardial infarction and stroke, although there was no significant trend seen relating to cardiovascular or all-cause mortality. The authors noted that this was the opposite to what was observed in the original SPRINT trial, where there was a reduction in cardiovascular mortality and heart failure but only a modest, nonsignificant impact on MI or stroke.

“Although the exact reasons remain unclear, this discrepancy might be explained in part by differences in study design, population characteristics, clinical practice pattern, or race or ethnic groups,” they suggested. “The generalizability of the SPRINT experience to multiple groups of various ethnic backgrounds warrants further investigations and is likely to be of considerable interest.”

Unlike the SPRINT trial, the Korean analysis did not look into the potential adverse effects of more aggressive blood pressure–lowering, but the authors noted that the SPRINT trial did see an increased incidence of more serious adverse events, including hypotension, syncope, and acute kidney injury.

“Therefore, beyond the BP target per se, several important factors should be considered for optimal BP management in the contemporary medical setting; for example, an integrated and systematic assessment of combined risk factors and baseline cardiovascular risk, concomitant preventive medical therapies, cost-effectiveness, clinician-patient discussions of the potential benefits and harms, or the clinical judgment of the treating physician.”

The National Evidence-Based Healthcare Collaborating Agency, Seoul, South Korea, funded the study. No conflicts of interest were declared.

Applying the more stringent SPRINT criteria to a general population of persons with hypertension would yield a significant reduction in the number of people meeting their treatment goals, although those who do would achieve a significant reduction in their risk of cardiovascular disease, a study published June 13 in the Journal of the American College of Cardiology has found.

Min Jung Ko, Ph.D., of the National Evidence-Based Healthcare Collaborating Agency in Seoul, Korea, and coauthors explored the relative impacts of SPRINT target of less than 120 mm Hg for hypertension treatments with the 2014 hypertension recommendations of the Eighth Joint National Committee of less than 140 mm Hg, using data from 13,346 individuals in the Korean National Health and Nutrition Examination Survey of 2008-2013, and 67,965 individuals in the Korean National Health Insurance Service health examinee cohort of 2007.

©Ingram Publishing/thinkstockphotos.com

The investigators found that 11.9% of adults with hypertension would meet the treatment goals of the SPRINT criteria, compared with 70.8% who would meet the 2014 recommendations.

However, the analysis showed that those who met the more aggressive SPRINT treatment goal of systolic BP below 120 mm Hg also had the lowest 10-year risk of a major cardiovascular event (6.2%), compared with 7.7% in those who met the 2014 targets but not the SPRINT targets, and 9.4% in those who failed to meet the 2014 treatment targets (J Am Coll Cardiol. 2016 Jun 13. doi 10.1016/j.jacc.2016.03.572).

After adjustment for factors such as age, diabetes, chronic kidney disease, hyperlipidemia, body mass index, and smoking, the least-controlled group showed a 62% increase in the risk of cardiovascular events, compared with the SPRINT criteria group. Those who met the 2014 criteria had a 17% greater risk than those who met the SPRINT criteria.

“Despite greater cardiovascular protection with intensive BP lowering, achieving SPRINT-defined BP goals might not be easy or practical because the target BP was not met in more than one-half of the participants in the intensive-treatment group,” the authors wrote.

Individuals who were older, female, or had diabetes, chronic kidney disease, or prevalent cardiovascular disease were more likely to meet the stricter goals of SPRINT (Systolic Blood Pressure Intervention Trial), in which combined cardiovascular events occurred in 5.2% of patients treated to a target systolic blood pressure of less than 120 mm Hg and 6.8% of patients treated to a target of less than 140 mm Hg (N Engl J Med. 2015;373:2103-16).

Researchers also noted a significant linear association between lesser blood pressure control and an increased risk of myocardial infarction and stroke, although there was no significant trend seen relating to cardiovascular or all-cause mortality. The authors noted that this was the opposite to what was observed in the original SPRINT trial, where there was a reduction in cardiovascular mortality and heart failure but only a modest, nonsignificant impact on MI or stroke.

“Although the exact reasons remain unclear, this discrepancy might be explained in part by differences in study design, population characteristics, clinical practice pattern, or race or ethnic groups,” they suggested. “The generalizability of the SPRINT experience to multiple groups of various ethnic backgrounds warrants further investigations and is likely to be of considerable interest.”

Unlike the SPRINT trial, the Korean analysis did not look into the potential adverse effects of more aggressive blood pressure–lowering, but the authors noted that the SPRINT trial did see an increased incidence of more serious adverse events, including hypotension, syncope, and acute kidney injury.

“Therefore, beyond the BP target per se, several important factors should be considered for optimal BP management in the contemporary medical setting; for example, an integrated and systematic assessment of combined risk factors and baseline cardiovascular risk, concomitant preventive medical therapies, cost-effectiveness, clinician-patient discussions of the potential benefits and harms, or the clinical judgment of the treating physician.”

The National Evidence-Based Healthcare Collaborating Agency, Seoul, South Korea, funded the study. No conflicts of interest were declared.

Applying the more stringent SPRINT criteria to a general population of persons with hypertension would yield a significant reduction in the number of people meeting their treatment goals, although those who do would achieve a significant reduction in their risk of cardiovascular disease, a study published June 13 in the Journal of the American College of Cardiology has found.

Min Jung Ko, Ph.D., of the National Evidence-Based Healthcare Collaborating Agency in Seoul, Korea, and coauthors explored the relative impacts of SPRINT target of less than 120 mm Hg for hypertension treatments with the 2014 hypertension recommendations of the Eighth Joint National Committee of less than 140 mm Hg, using data from 13,346 individuals in the Korean National Health and Nutrition Examination Survey of 2008-2013, and 67,965 individuals in the Korean National Health Insurance Service health examinee cohort of 2007.

©Ingram Publishing/thinkstockphotos.com

The investigators found that 11.9% of adults with hypertension would meet the treatment goals of the SPRINT criteria, compared with 70.8% who would meet the 2014 recommendations.

However, the analysis showed that those who met the more aggressive SPRINT treatment goal of systolic BP below 120 mm Hg also had the lowest 10-year risk of a major cardiovascular event (6.2%), compared with 7.7% in those who met the 2014 targets but not the SPRINT targets, and 9.4% in those who failed to meet the 2014 treatment targets (J Am Coll Cardiol. 2016 Jun 13. doi 10.1016/j.jacc.2016.03.572).

After adjustment for factors such as age, diabetes, chronic kidney disease, hyperlipidemia, body mass index, and smoking, the least-controlled group showed a 62% increase in the risk of cardiovascular events, compared with the SPRINT criteria group. Those who met the 2014 criteria had a 17% greater risk than those who met the SPRINT criteria.

“Despite greater cardiovascular protection with intensive BP lowering, achieving SPRINT-defined BP goals might not be easy or practical because the target BP was not met in more than one-half of the participants in the intensive-treatment group,” the authors wrote.

Individuals who were older, female, or had diabetes, chronic kidney disease, or prevalent cardiovascular disease were more likely to meet the stricter goals of SPRINT (Systolic Blood Pressure Intervention Trial), in which combined cardiovascular events occurred in 5.2% of patients treated to a target systolic blood pressure of less than 120 mm Hg and 6.8% of patients treated to a target of less than 140 mm Hg (N Engl J Med. 2015;373:2103-16).

Researchers also noted a significant linear association between lesser blood pressure control and an increased risk of myocardial infarction and stroke, although there was no significant trend seen relating to cardiovascular or all-cause mortality. The authors noted that this was the opposite to what was observed in the original SPRINT trial, where there was a reduction in cardiovascular mortality and heart failure but only a modest, nonsignificant impact on MI or stroke.

“Although the exact reasons remain unclear, this discrepancy might be explained in part by differences in study design, population characteristics, clinical practice pattern, or race or ethnic groups,” they suggested. “The generalizability of the SPRINT experience to multiple groups of various ethnic backgrounds warrants further investigations and is likely to be of considerable interest.”

Unlike the SPRINT trial, the Korean analysis did not look into the potential adverse effects of more aggressive blood pressure–lowering, but the authors noted that the SPRINT trial did see an increased incidence of more serious adverse events, including hypotension, syncope, and acute kidney injury.

“Therefore, beyond the BP target per se, several important factors should be considered for optimal BP management in the contemporary medical setting; for example, an integrated and systematic assessment of combined risk factors and baseline cardiovascular risk, concomitant preventive medical therapies, cost-effectiveness, clinician-patient discussions of the potential benefits and harms, or the clinical judgment of the treating physician.”

The National Evidence-Based Healthcare Collaborating Agency, Seoul, South Korea, funded the study. No conflicts of interest were declared.

LOS ANGELES – The use of locoregional tissue flaps in combination with abdominoperineal resection was associated with higher rates of perioperative complications, longer hospital stays, and higher total hospital charges, compared with patients who did not undergo tissue flap reconstruction, an analysis of national data showed.

The findings come at a time when closure of perineal wounds with tissue flaps is an increasingly common approach, especially in academic institutions, Dr. Nicole Lopez said at the annual meeting of the American Society of Colon and Rectal Surgeons. “The role of selection bias in this [study] is difficult to determine, but I think it’s important that we clarify the utility of this technique before more widespread adoption of the approach,” she said.

According to Dr. Lopez of the department of surgery at the University of North Carolina, Chapel Hill, perineal wound complications can occur in 16%-49% of patients undergoing abdominoperineal resection. Contributing factors include noncollapsible dead space, bacterial contamination, wound characteristics, and patient comorbidities.

In an effort to identify national trends in the use of tissue flaps in patients undergoing abdominoperineal resection for rectal or anal cancer, as well as the effect of this approach on perioperative complications, length of stay, and total hospital charges, Dr. Lopez and her associates used the National Inpatient Sample to identify patients aged 18-80 years who were treated between 2000 and 2013. They excluded patients undergoing nonelective procedures or additional pelvic organ resections. Patients who received a tissue flap were compared with those who did not.

Dr. Lopez reported results from 298 patients who received a tissue flap graft and 12,107 who did not. Variables significantly associated with receiving a tissue flap, compared with not receiving one, were being male (73% vs. 66%, respectively; P =. 01), having anal cancer (32% vs. 11%; P less than .0001), being a smoker (34% vs. 23%; P less than .0001), undergoing the procedure in a large hospital (75% vs. 67%; P = .003), and undergoing the procedure in an urban teaching hospital (89% vs. 53%; P less than .0001).

The researchers also found that the number of concurrent tissue flaps performed rose significantly during the study period, from 0.4% in 2000 to 6% in 2013 (P less than .0001). “This was most noted in teaching institutions, compared with nonteaching institutions,” Dr. Lopez said.

Bivariate analysis revealed that, compared with patients who did not receive tissue flaps, those who did had higher rates of postoperative complications (43% vs. 33%, respectively; P less than .0001), a longer hospital stay (mean of 9 vs. 7 days; P less than .001), and higher total hospital charges (mean of $67,200 vs. $42,300; P less than .001). These trends persisted on multivariate analysis. Specifically, patients who received tissue flaps were 4.14 times more likely to have wound complications, had a length of stay that averaged an additional 2.78 days, and had $28,000 more in total hospital charges.

“The extended duration of the study enables evaluation of trends over time, and this is the first study that analyzes the costs associated with these procedures,” Dr. Lopez said. She acknowledged certain limitations of the study, including its retrospective, nonrandomized design and the potential for selection bias. In addition, the National Inpatient Sample “is susceptible to coding errors, a lack of patient-specific oncologic history, and the inability to assess postdischarge occurrences, since this only looks at inpatient stays.”

Dr. Lopez reported having no financial disclosures.

[email protected]

LOS ANGELES – The use of locoregional tissue flaps in combination with abdominoperineal resection was associated with higher rates of perioperative complications, longer hospital stays, and higher total hospital charges, compared with patients who did not undergo tissue flap reconstruction, an analysis of national data showed.

The findings come at a time when closure of perineal wounds with tissue flaps is an increasingly common approach, especially in academic institutions, Dr. Nicole Lopez said at the annual meeting of the American Society of Colon and Rectal Surgeons. “The role of selection bias in this [study] is difficult to determine, but I think it’s important that we clarify the utility of this technique before more widespread adoption of the approach,” she said.

According to Dr. Lopez of the department of surgery at the University of North Carolina, Chapel Hill, perineal wound complications can occur in 16%-49% of patients undergoing abdominoperineal resection. Contributing factors include noncollapsible dead space, bacterial contamination, wound characteristics, and patient comorbidities.

In an effort to identify national trends in the use of tissue flaps in patients undergoing abdominoperineal resection for rectal or anal cancer, as well as the effect of this approach on perioperative complications, length of stay, and total hospital charges, Dr. Lopez and her associates used the National Inpatient Sample to identify patients aged 18-80 years who were treated between 2000 and 2013. They excluded patients undergoing nonelective procedures or additional pelvic organ resections. Patients who received a tissue flap were compared with those who did not.

Dr. Lopez reported results from 298 patients who received a tissue flap graft and 12,107 who did not. Variables significantly associated with receiving a tissue flap, compared with not receiving one, were being male (73% vs. 66%, respectively; P =. 01), having anal cancer (32% vs. 11%; P less than .0001), being a smoker (34% vs. 23%; P less than .0001), undergoing the procedure in a large hospital (75% vs. 67%; P = .003), and undergoing the procedure in an urban teaching hospital (89% vs. 53%; P less than .0001).

The researchers also found that the number of concurrent tissue flaps performed rose significantly during the study period, from 0.4% in 2000 to 6% in 2013 (P less than .0001). “This was most noted in teaching institutions, compared with nonteaching institutions,” Dr. Lopez said.

Bivariate analysis revealed that, compared with patients who did not receive tissue flaps, those who did had higher rates of postoperative complications (43% vs. 33%, respectively; P less than .0001), a longer hospital stay (mean of 9 vs. 7 days; P less than .001), and higher total hospital charges (mean of $67,200 vs. $42,300; P less than .001). These trends persisted on multivariate analysis. Specifically, patients who received tissue flaps were 4.14 times more likely to have wound complications, had a length of stay that averaged an additional 2.78 days, and had $28,000 more in total hospital charges.

“The extended duration of the study enables evaluation of trends over time, and this is the first study that analyzes the costs associated with these procedures,” Dr. Lopez said. She acknowledged certain limitations of the study, including its retrospective, nonrandomized design and the potential for selection bias. In addition, the National Inpatient Sample “is susceptible to coding errors, a lack of patient-specific oncologic history, and the inability to assess postdischarge occurrences, since this only looks at inpatient stays.”

Dr. Lopez reported having no financial disclosures.

[email protected]

LOS ANGELES – The use of locoregional tissue flaps in combination with abdominoperineal resection was associated with higher rates of perioperative complications, longer hospital stays, and higher total hospital charges, compared with patients who did not undergo tissue flap reconstruction, an analysis of national data showed.

The findings come at a time when closure of perineal wounds with tissue flaps is an increasingly common approach, especially in academic institutions, Dr. Nicole Lopez said at the annual meeting of the American Society of Colon and Rectal Surgeons. “The role of selection bias in this [study] is difficult to determine, but I think it’s important that we clarify the utility of this technique before more widespread adoption of the approach,” she said.

According to Dr. Lopez of the department of surgery at the University of North Carolina, Chapel Hill, perineal wound complications can occur in 16%-49% of patients undergoing abdominoperineal resection. Contributing factors include noncollapsible dead space, bacterial contamination, wound characteristics, and patient comorbidities.

In an effort to identify national trends in the use of tissue flaps in patients undergoing abdominoperineal resection for rectal or anal cancer, as well as the effect of this approach on perioperative complications, length of stay, and total hospital charges, Dr. Lopez and her associates used the National Inpatient Sample to identify patients aged 18-80 years who were treated between 2000 and 2013. They excluded patients undergoing nonelective procedures or additional pelvic organ resections. Patients who received a tissue flap were compared with those who did not.

Dr. Lopez reported results from 298 patients who received a tissue flap graft and 12,107 who did not. Variables significantly associated with receiving a tissue flap, compared with not receiving one, were being male (73% vs. 66%, respectively; P =. 01), having anal cancer (32% vs. 11%; P less than .0001), being a smoker (34% vs. 23%; P less than .0001), undergoing the procedure in a large hospital (75% vs. 67%; P = .003), and undergoing the procedure in an urban teaching hospital (89% vs. 53%; P less than .0001).

The researchers also found that the number of concurrent tissue flaps performed rose significantly during the study period, from 0.4% in 2000 to 6% in 2013 (P less than .0001). “This was most noted in teaching institutions, compared with nonteaching institutions,” Dr. Lopez said.

Bivariate analysis revealed that, compared with patients who did not receive tissue flaps, those who did had higher rates of postoperative complications (43% vs. 33%, respectively; P less than .0001), a longer hospital stay (mean of 9 vs. 7 days; P less than .001), and higher total hospital charges (mean of $67,200 vs. $42,300; P less than .001). These trends persisted on multivariate analysis. Specifically, patients who received tissue flaps were 4.14 times more likely to have wound complications, had a length of stay that averaged an additional 2.78 days, and had $28,000 more in total hospital charges.

“The extended duration of the study enables evaluation of trends over time, and this is the first study that analyzes the costs associated with these procedures,” Dr. Lopez said. She acknowledged certain limitations of the study, including its retrospective, nonrandomized design and the potential for selection bias. In addition, the National Inpatient Sample “is susceptible to coding errors, a lack of patient-specific oncologic history, and the inability to assess postdischarge occurrences, since this only looks at inpatient stays.”

Dr. Lopez reported having no financial disclosures.

[email protected]

For individual stories every day and to see the complete daily issues of Vascular Connections, the official on-site newspaper of the Vascular Annual Meeting, check us out at our website.

Featuring the President’s Address, the E. Stanley Crawford Critical Issues Forum and ‘person on the street’ interviews, as well as plenary talks and breakfast sessions, it is your one stop shopping for coverage.

And be sure to follow our continuing advanced coverage of the Vascular Annual Meeting in future issues of Vascular Specialist.

For individual stories every day and to see the complete daily issues of Vascular Connections, the official on-site newspaper of the Vascular Annual Meeting, check us out at our website.

Featuring the President’s Address, the E. Stanley Crawford Critical Issues Forum and ‘person on the street’ interviews, as well as plenary talks and breakfast sessions, it is your one stop shopping for coverage.

And be sure to follow our continuing advanced coverage of the Vascular Annual Meeting in future issues of Vascular Specialist.

For individual stories every day and to see the complete daily issues of Vascular Connections, the official on-site newspaper of the Vascular Annual Meeting, check us out at our website.

Featuring the President’s Address, the E. Stanley Crawford Critical Issues Forum and ‘person on the street’ interviews, as well as plenary talks and breakfast sessions, it is your one stop shopping for coverage.

And be sure to follow our continuing advanced coverage of the Vascular Annual Meeting in future issues of Vascular Specialist.

NEW ORLEANS – The prevalence of autism spectrum disorder in children and adolescents with type 1 diabetes appears to be similar to that in the general pediatric population, according to a study conducted in Colorado.

“There is no known literature on management of patients with autism spectrum disorder and type 1 diabetes to assess if management is different in this population,” Dr. Shideh Majidi said in an interview at the annual scientific sessions of the American Diabetes Association.

Doug Brunk/Frontline Medical News

In what she said is the first study of its kind conducted in the United States, Dr. Majidi and her associates investigated the prevalence of autism spectrum disorder (ASD) in a large diabetes center to better understand the diabetes characteristics and management of those with both type 1 diabetes and ASD. The researchers evaluated 2,360 patients aged 18 months to 18 years cared for at the Barbara Davis Center for Childhood Diabetes at the University of Colorado, Aurora. Of the 2,360 patients, 30 (28 males and 2 females) had ASD, for a prevalence of 1 in 87 (1.15%). This was similar to the prevalence of ASD in the general Colorado population, which is estimated to be 1 in 85 (1.18%).

Patients with type 1 diabetes and ASD had a mean age of 12.9 years and had the disease for a mean of 5 years. There were fewer females with type 1 diabetes and ASD, compared with those who had type 1 diabetes only (7% vs. 48%, respectively; P less than .001).

Compared with patients who had type 1 diabetes, those with type 1 diabetes and ASD had similar hemoglobin A_1c levels (a median of 8.2% vs. 8.8%, P = .17) and number of blood glucose tests per day (a median of 5.1 vs. 4.9, P = .32), but were less likely to be on an insulin pump (43.3% vs. 57%, P = .14).

The overall findings suggest that management in patients with ASD and type 1 diabetes does not necessarily need to differ from those without ASD. “For instance, it is possible for ASD patients to do well on an insulin pump,” said Dr. Majidi, who is a pediatric endocrinologist at the Barbara Davis Center for Childhood Diabetes. “Also, A_1c and blood sugar checks are similar between those with and without ASD, and thus similar intensive management can be recommended for this group. So just like in patients without ASD, diabetes should be managed on an individual basis, looking at individual needs, but having a diagnosis of ASD does not have to limit our views as providers of what types of management we can offer for ideal diabetes management.”

She acknowledged certain limitations of the study, including its single-center design and relatively small sample size. “It would be beneficial to obtain larger numbers of patients with ASD and type 1 diabetes via multicenter studies in order to get a larger group of patients with both diagnoses, in order to see if our results remain when looking on a larger scale.”

In a video interview at the meeting, Dr. Majidi and Dr. Kelly Stanek of the Barbara Davis Center for Childhood Diabetes discussed the study's findings and the next steps for research, including a closer examination of the challenges parents face in caring for children with type 1 diabetes and ASD.

Dr. Majidi and Dr. Stanek reported having no relevant financial disclosures.

[email protected]

NEW ORLEANS – The prevalence of autism spectrum disorder in children and adolescents with type 1 diabetes appears to be similar to that in the general pediatric population, according to a study conducted in Colorado.

“There is no known literature on management of patients with autism spectrum disorder and type 1 diabetes to assess if management is different in this population,” Dr. Shideh Majidi said in an interview at the annual scientific sessions of the American Diabetes Association.

Doug Brunk/Frontline Medical News

In what she said is the first study of its kind conducted in the United States, Dr. Majidi and her associates investigated the prevalence of autism spectrum disorder (ASD) in a large diabetes center to better understand the diabetes characteristics and management of those with both type 1 diabetes and ASD. The researchers evaluated 2,360 patients aged 18 months to 18 years cared for at the Barbara Davis Center for Childhood Diabetes at the University of Colorado, Aurora. Of the 2,360 patients, 30 (28 males and 2 females) had ASD, for a prevalence of 1 in 87 (1.15%). This was similar to the prevalence of ASD in the general Colorado population, which is estimated to be 1 in 85 (1.18%).

Patients with type 1 diabetes and ASD had a mean age of 12.9 years and had the disease for a mean of 5 years. There were fewer females with type 1 diabetes and ASD, compared with those who had type 1 diabetes only (7% vs. 48%, respectively; P less than .001).

Compared with patients who had type 1 diabetes, those with type 1 diabetes and ASD had similar hemoglobin A_1c levels (a median of 8.2% vs. 8.8%, P = .17) and number of blood glucose tests per day (a median of 5.1 vs. 4.9, P = .32), but were less likely to be on an insulin pump (43.3% vs. 57%, P = .14).

The overall findings suggest that management in patients with ASD and type 1 diabetes does not necessarily need to differ from those without ASD. “For instance, it is possible for ASD patients to do well on an insulin pump,” said Dr. Majidi, who is a pediatric endocrinologist at the Barbara Davis Center for Childhood Diabetes. “Also, A_1c and blood sugar checks are similar between those with and without ASD, and thus similar intensive management can be recommended for this group. So just like in patients without ASD, diabetes should be managed on an individual basis, looking at individual needs, but having a diagnosis of ASD does not have to limit our views as providers of what types of management we can offer for ideal diabetes management.”

She acknowledged certain limitations of the study, including its single-center design and relatively small sample size. “It would be beneficial to obtain larger numbers of patients with ASD and type 1 diabetes via multicenter studies in order to get a larger group of patients with both diagnoses, in order to see if our results remain when looking on a larger scale.”

In a video interview at the meeting, Dr. Majidi and Dr. Kelly Stanek of the Barbara Davis Center for Childhood Diabetes discussed the study's findings and the next steps for research, including a closer examination of the challenges parents face in caring for children with type 1 diabetes and ASD.

Dr. Majidi and Dr. Stanek reported having no relevant financial disclosures.

[email protected]

NEW ORLEANS – The prevalence of autism spectrum disorder in children and adolescents with type 1 diabetes appears to be similar to that in the general pediatric population, according to a study conducted in Colorado.

“There is no known literature on management of patients with autism spectrum disorder and type 1 diabetes to assess if management is different in this population,” Dr. Shideh Majidi said in an interview at the annual scientific sessions of the American Diabetes Association.

Doug Brunk/Frontline Medical News

In what she said is the first study of its kind conducted in the United States, Dr. Majidi and her associates investigated the prevalence of autism spectrum disorder (ASD) in a large diabetes center to better understand the diabetes characteristics and management of those with both type 1 diabetes and ASD. The researchers evaluated 2,360 patients aged 18 months to 18 years cared for at the Barbara Davis Center for Childhood Diabetes at the University of Colorado, Aurora. Of the 2,360 patients, 30 (28 males and 2 females) had ASD, for a prevalence of 1 in 87 (1.15%). This was similar to the prevalence of ASD in the general Colorado population, which is estimated to be 1 in 85 (1.18%).

Patients with type 1 diabetes and ASD had a mean age of 12.9 years and had the disease for a mean of 5 years. There were fewer females with type 1 diabetes and ASD, compared with those who had type 1 diabetes only (7% vs. 48%, respectively; P less than .001).

Compared with patients who had type 1 diabetes, those with type 1 diabetes and ASD had similar hemoglobin A_1c levels (a median of 8.2% vs. 8.8%, P = .17) and number of blood glucose tests per day (a median of 5.1 vs. 4.9, P = .32), but were less likely to be on an insulin pump (43.3% vs. 57%, P = .14).

The overall findings suggest that management in patients with ASD and type 1 diabetes does not necessarily need to differ from those without ASD. “For instance, it is possible for ASD patients to do well on an insulin pump,” said Dr. Majidi, who is a pediatric endocrinologist at the Barbara Davis Center for Childhood Diabetes. “Also, A_1c and blood sugar checks are similar between those with and without ASD, and thus similar intensive management can be recommended for this group. So just like in patients without ASD, diabetes should be managed on an individual basis, looking at individual needs, but having a diagnosis of ASD does not have to limit our views as providers of what types of management we can offer for ideal diabetes management.”

She acknowledged certain limitations of the study, including its single-center design and relatively small sample size. “It would be beneficial to obtain larger numbers of patients with ASD and type 1 diabetes via multicenter studies in order to get a larger group of patients with both diagnoses, in order to see if our results remain when looking on a larger scale.”

In a video interview at the meeting, Dr. Majidi and Dr. Kelly Stanek of the Barbara Davis Center for Childhood Diabetes discussed the study's findings and the next steps for research, including a closer examination of the challenges parents face in caring for children with type 1 diabetes and ASD.

Dr. Majidi and Dr. Stanek reported having no relevant financial disclosures.

[email protected]

ORLANDO – In the case of transgender youth and adults – those with what is now called gender dysphoria – physicians are faced with treating individuals who generally have no physical disease or abnormalities.

Endocrinologists are the professionals who are often tasked with the medical aspects of treating gender dysphoria. In an effort to help them understand the underpinnings and aspects of the conditions, Dr. Stephen Rosenthal, professor of pediatrics and medical director of the Child and Adolescent Medical Gender Center at the University of California, San Francisco, reviewed current knowledge about the biological basis for gender identity, current treatment models, and barriers to care of patients with gender dysphoria.

Speaking at the annual meeting of the American Association of Clinical Endocrinologists, Dr. Rosenthal said the dysphoria derives from the significant emotional distress that may be associated with a transgender identity, essentially from the social and psychological pressures of being born and living in a body (the “natal sex”) that does not match an individual’s gender identity, defined as one’s fundamental sense of self as male or female. “It’s not always limited to those two choices, and it’s not always binary,” he said, since individuals may identify with aspects of both or, at times, neither gender.

He defined some terms, such as transgender, which refers to a transient or persistent identification with gender different from the one others assume based on physical sex characteristics at birth. That gender becomes the one of rearing, which may not be how the individual feels growing up. Gender identity should not be confused with sexual identity or orientation because people of any gender can have any sexual orientation.

“Gender Identity Disorder,” a term used in the DSM IV (Diagnostic and Statistical Manual of Mental Disorders IV) has been replaced by “Gender Dysphoria in Children” in DSM 5. And even that term may be revised since transgender identity in itself is not a pathology.

In one survey of 28,176 people, 0.5% self-identified as transgender. Another survey showed statistically significant risks associated with being transgender. Comparing 180 transgender youth with 180 non–transgender youth (average age, 19.6 years; range, 12-29 years), researchers found a two- to threefold increased risk of depression, anxiety disorder, suicidal ideation, suicide attempt, and self- harm without lethal intent among the transgender youths. Parental support helped alleviate some of these risks, especially suicide attempts, but did not eliminate them entirely; that support also contributed to better mental and physical health, improved self-esteem, and even adequate food and housing for transgender adolescents.

Clues to biological influences

A complex interplay of biological, environmental, and cultural factors affect the determination of gender identity. Evidence points to the role of biology in gender identity development through studies of genetics, hormones, and the brain, but none of these is a “litmus test” for gender identity, Dr. Rosenthal said.

A study of 23 monozygotic twin pairs, 21 same-sex dizygotic twin pairs, and 7 opposite-sex twin pairs showed a 39.1% concordance for gender dysphoria among the monozygotic twins but none for the other sets.

Most transgender individuals do not have any obvious disorder of sexual development, but that is not to rule out a role of prenatal or postnatal androgens (specifically enzymes of the steroid pathways), androgen insensitivity, or extragonadal sources of androgen, as in congenital adrenal hyperplasia (CAH). Among 250 46XX females with CAH raised as female, 5.2% had male gender identity or gender dysphoria (a 10- to 20-fold increased risk vs. controls), suggesting a possible role for prenatal androgens in gender identity development.

A neurobiological basis for transgender is supported by some studies of sexually dimorphic brain structures but is by no means conclusive. Numerous studies of gray and white matter showed that sexually dimorphic structures are more closely aligned with gender identity than with physical sex (even before cross-sex hormones have been applied). But morphometry on areas of the brain that show the largest sex differences found that variability was more prevalent than was consistency in the 1,400 brains studied.

Tests of “functional sexual dimorphism” used PET or MRI to measure changes in regional blood flow in the anterior hypothalamus when control adolescent girls or boys or those with gender dysphoria were asked to smell substances containing pheromones of the opposite sex (for girls: androstadienone in a mixture of male sweat and semen; for boys: estrogen-like compounds in urine of pregnant women). Both girls and boys with gender dysphoria had responses significantly different from those of their respective controls.

Natural history of gender dysphoria

Dr. Rosenthal said symptoms of gender dysphoria in prepubertal children decrease or disappear in 70%-95% of cases, but if they persist into early puberty, the individual is likely to be transgender as an adult. Children with more intense gender dysphoria and those who believed they “were” the opposite sex were more likely to have persistent gender dysphoria as adults. In a study based on parents’ completed measures, prepubescent transgender boys and girls who have socially transitioned had depression scores no higher than those of matched nontransgender controls. They had much lower anxiety and depression, compared with non–socially transitioned transgender historical control children.

Medically induced sexual transitioning

For pediatric and adolescent transsexual patients who express a desire to transition to the opposite sex, an Endocrine Society clinical practice guideline on endocrine treatment recommends that a mental health professional make the diagnosis of gender dysphoria. Then the medical provider needs to ensure that the patient understands the consequences of hormone suppression and cross-sex hormone therapy prior to beginning treatments. Only after early puberty has begun should gonadotropin-releasing hormone (GnRH) agonists be used to suppress pubertal hormones. At about age 16 years, cross-sex hormone treatments can begin, with surgery deferred at least until age 18 years if the patient desires full transitioning.

A Dutch study (Pediatrics. 2014 Oct. 134:696-704) showed that after gender reassignment, in young adulthood, gender dysphoria “was alleviated and psychological functioning had steadily improved. Well-being was similar to or better than same-age young adults from the general population.” No patients reported any regret during any stages of the sex-reassignment protocol.

There is some concern about adverse effects of the GnRH agonists, such as on bone mass and health, the brain, and fertility. But no detrimental effects were observed in a study on executive functioning, which undergoes significant development during puberty, in either male-to-female or female-to-male individuals.

Future parenthood may be an option if the patient is old enough. “We always encourage them to either freeze sperm, or we can potentially freeze eggs before embarking on phenotypic transition,” Dr. Rosenthal said. But allowing a patient to get to a stage of spermatogenesis or egg production would allow puberty to proceed to a significant degree. “So one of the exciting areas of research is actually taking prepubertal tissue … [in mice] they took neonatal testicular tissue and they basically showed you could take it all the way through the steps of full maturation and get progeny that were reproductively competent,” he said. Similar studies are being done in humans, mainly because there is interest in preserving fertility of children undergoing cancer treatments.

Barriers to care for transgender youth include limited access to medications, including off-label use, great expense, and insurance company denials of reimbursement. There are also relatively few clinical programs and a lack of training for health care professionals, as well as prejudice and misunderstanding, even among professionals.

ORLANDO – In the case of transgender youth and adults – those with what is now called gender dysphoria – physicians are faced with treating individuals who generally have no physical disease or abnormalities.

Endocrinologists are the professionals who are often tasked with the medical aspects of treating gender dysphoria. In an effort to help them understand the underpinnings and aspects of the conditions, Dr. Stephen Rosenthal, professor of pediatrics and medical director of the Child and Adolescent Medical Gender Center at the University of California, San Francisco, reviewed current knowledge about the biological basis for gender identity, current treatment models, and barriers to care of patients with gender dysphoria.

Speaking at the annual meeting of the American Association of Clinical Endocrinologists, Dr. Rosenthal said the dysphoria derives from the significant emotional distress that may be associated with a transgender identity, essentially from the social and psychological pressures of being born and living in a body (the “natal sex”) that does not match an individual’s gender identity, defined as one’s fundamental sense of self as male or female. “It’s not always limited to those two choices, and it’s not always binary,” he said, since individuals may identify with aspects of both or, at times, neither gender.

He defined some terms, such as transgender, which refers to a transient or persistent identification with gender different from the one others assume based on physical sex characteristics at birth. That gender becomes the one of rearing, which may not be how the individual feels growing up. Gender identity should not be confused with sexual identity or orientation because people of any gender can have any sexual orientation.

“Gender Identity Disorder,” a term used in the DSM IV (Diagnostic and Statistical Manual of Mental Disorders IV) has been replaced by “Gender Dysphoria in Children” in DSM 5. And even that term may be revised since transgender identity in itself is not a pathology.

In one survey of 28,176 people, 0.5% self-identified as transgender. Another survey showed statistically significant risks associated with being transgender. Comparing 180 transgender youth with 180 non–transgender youth (average age, 19.6 years; range, 12-29 years), researchers found a two- to threefold increased risk of depression, anxiety disorder, suicidal ideation, suicide attempt, and self- harm without lethal intent among the transgender youths. Parental support helped alleviate some of these risks, especially suicide attempts, but did not eliminate them entirely; that support also contributed to better mental and physical health, improved self-esteem, and even adequate food and housing for transgender adolescents.

Clues to biological influences

A complex interplay of biological, environmental, and cultural factors affect the determination of gender identity. Evidence points to the role of biology in gender identity development through studies of genetics, hormones, and the brain, but none of these is a “litmus test” for gender identity, Dr. Rosenthal said.

A study of 23 monozygotic twin pairs, 21 same-sex dizygotic twin pairs, and 7 opposite-sex twin pairs showed a 39.1% concordance for gender dysphoria among the monozygotic twins but none for the other sets.

Most transgender individuals do not have any obvious disorder of sexual development, but that is not to rule out a role of prenatal or postnatal androgens (specifically enzymes of the steroid pathways), androgen insensitivity, or extragonadal sources of androgen, as in congenital adrenal hyperplasia (CAH). Among 250 46XX females with CAH raised as female, 5.2% had male gender identity or gender dysphoria (a 10- to 20-fold increased risk vs. controls), suggesting a possible role for prenatal androgens in gender identity development.

A neurobiological basis for transgender is supported by some studies of sexually dimorphic brain structures but is by no means conclusive. Numerous studies of gray and white matter showed that sexually dimorphic structures are more closely aligned with gender identity than with physical sex (even before cross-sex hormones have been applied). But morphometry on areas of the brain that show the largest sex differences found that variability was more prevalent than was consistency in the 1,400 brains studied.

Tests of “functional sexual dimorphism” used PET or MRI to measure changes in regional blood flow in the anterior hypothalamus when control adolescent girls or boys or those with gender dysphoria were asked to smell substances containing pheromones of the opposite sex (for girls: androstadienone in a mixture of male sweat and semen; for boys: estrogen-like compounds in urine of pregnant women). Both girls and boys with gender dysphoria had responses significantly different from those of their respective controls.

Natural history of gender dysphoria

Dr. Rosenthal said symptoms of gender dysphoria in prepubertal children decrease or disappear in 70%-95% of cases, but if they persist into early puberty, the individual is likely to be transgender as an adult. Children with more intense gender dysphoria and those who believed they “were” the opposite sex were more likely to have persistent gender dysphoria as adults. In a study based on parents’ completed measures, prepubescent transgender boys and girls who have socially transitioned had depression scores no higher than those of matched nontransgender controls. They had much lower anxiety and depression, compared with non–socially transitioned transgender historical control children.

Medically induced sexual transitioning

For pediatric and adolescent transsexual patients who express a desire to transition to the opposite sex, an Endocrine Society clinical practice guideline on endocrine treatment recommends that a mental health professional make the diagnosis of gender dysphoria. Then the medical provider needs to ensure that the patient understands the consequences of hormone suppression and cross-sex hormone therapy prior to beginning treatments. Only after early puberty has begun should gonadotropin-releasing hormone (GnRH) agonists be used to suppress pubertal hormones. At about age 16 years, cross-sex hormone treatments can begin, with surgery deferred at least until age 18 years if the patient desires full transitioning.

A Dutch study (Pediatrics. 2014 Oct. 134:696-704) showed that after gender reassignment, in young adulthood, gender dysphoria “was alleviated and psychological functioning had steadily improved. Well-being was similar to or better than same-age young adults from the general population.” No patients reported any regret during any stages of the sex-reassignment protocol.

There is some concern about adverse effects of the GnRH agonists, such as on bone mass and health, the brain, and fertility. But no detrimental effects were observed in a study on executive functioning, which undergoes significant development during puberty, in either male-to-female or female-to-male individuals.

Future parenthood may be an option if the patient is old enough. “We always encourage them to either freeze sperm, or we can potentially freeze eggs before embarking on phenotypic transition,” Dr. Rosenthal said. But allowing a patient to get to a stage of spermatogenesis or egg production would allow puberty to proceed to a significant degree. “So one of the exciting areas of research is actually taking prepubertal tissue … [in mice] they took neonatal testicular tissue and they basically showed you could take it all the way through the steps of full maturation and get progeny that were reproductively competent,” he said. Similar studies are being done in humans, mainly because there is interest in preserving fertility of children undergoing cancer treatments.

Barriers to care for transgender youth include limited access to medications, including off-label use, great expense, and insurance company denials of reimbursement. There are also relatively few clinical programs and a lack of training for health care professionals, as well as prejudice and misunderstanding, even among professionals.

ORLANDO – In the case of transgender youth and adults – those with what is now called gender dysphoria – physicians are faced with treating individuals who generally have no physical disease or abnormalities.

Endocrinologists are the professionals who are often tasked with the medical aspects of treating gender dysphoria. In an effort to help them understand the underpinnings and aspects of the conditions, Dr. Stephen Rosenthal, professor of pediatrics and medical director of the Child and Adolescent Medical Gender Center at the University of California, San Francisco, reviewed current knowledge about the biological basis for gender identity, current treatment models, and barriers to care of patients with gender dysphoria.

Speaking at the annual meeting of the American Association of Clinical Endocrinologists, Dr. Rosenthal said the dysphoria derives from the significant emotional distress that may be associated with a transgender identity, essentially from the social and psychological pressures of being born and living in a body (the “natal sex”) that does not match an individual’s gender identity, defined as one’s fundamental sense of self as male or female. “It’s not always limited to those two choices, and it’s not always binary,” he said, since individuals may identify with aspects of both or, at times, neither gender.

He defined some terms, such as transgender, which refers to a transient or persistent identification with gender different from the one others assume based on physical sex characteristics at birth. That gender becomes the one of rearing, which may not be how the individual feels growing up. Gender identity should not be confused with sexual identity or orientation because people of any gender can have any sexual orientation.

“Gender Identity Disorder,” a term used in the DSM IV (Diagnostic and Statistical Manual of Mental Disorders IV) has been replaced by “Gender Dysphoria in Children” in DSM 5. And even that term may be revised since transgender identity in itself is not a pathology.

In one survey of 28,176 people, 0.5% self-identified as transgender. Another survey showed statistically significant risks associated with being transgender. Comparing 180 transgender youth with 180 non–transgender youth (average age, 19.6 years; range, 12-29 years), researchers found a two- to threefold increased risk of depression, anxiety disorder, suicidal ideation, suicide attempt, and self- harm without lethal intent among the transgender youths. Parental support helped alleviate some of these risks, especially suicide attempts, but did not eliminate them entirely; that support also contributed to better mental and physical health, improved self-esteem, and even adequate food and housing for transgender adolescents.

Clues to biological influences

A complex interplay of biological, environmental, and cultural factors affect the determination of gender identity. Evidence points to the role of biology in gender identity development through studies of genetics, hormones, and the brain, but none of these is a “litmus test” for gender identity, Dr. Rosenthal said.

A study of 23 monozygotic twin pairs, 21 same-sex dizygotic twin pairs, and 7 opposite-sex twin pairs showed a 39.1% concordance for gender dysphoria among the monozygotic twins but none for the other sets.

Most transgender individuals do not have any obvious disorder of sexual development, but that is not to rule out a role of prenatal or postnatal androgens (specifically enzymes of the steroid pathways), androgen insensitivity, or extragonadal sources of androgen, as in congenital adrenal hyperplasia (CAH). Among 250 46XX females with CAH raised as female, 5.2% had male gender identity or gender dysphoria (a 10- to 20-fold increased risk vs. controls), suggesting a possible role for prenatal androgens in gender identity development.

A neurobiological basis for transgender is supported by some studies of sexually dimorphic brain structures but is by no means conclusive. Numerous studies of gray and white matter showed that sexually dimorphic structures are more closely aligned with gender identity than with physical sex (even before cross-sex hormones have been applied). But morphometry on areas of the brain that show the largest sex differences found that variability was more prevalent than was consistency in the 1,400 brains studied.

Tests of “functional sexual dimorphism” used PET or MRI to measure changes in regional blood flow in the anterior hypothalamus when control adolescent girls or boys or those with gender dysphoria were asked to smell substances containing pheromones of the opposite sex (for girls: androstadienone in a mixture of male sweat and semen; for boys: estrogen-like compounds in urine of pregnant women). Both girls and boys with gender dysphoria had responses significantly different from those of their respective controls.

Natural history of gender dysphoria

Dr. Rosenthal said symptoms of gender dysphoria in prepubertal children decrease or disappear in 70%-95% of cases, but if they persist into early puberty, the individual is likely to be transgender as an adult. Children with more intense gender dysphoria and those who believed they “were” the opposite sex were more likely to have persistent gender dysphoria as adults. In a study based on parents’ completed measures, prepubescent transgender boys and girls who have socially transitioned had depression scores no higher than those of matched nontransgender controls. They had much lower anxiety and depression, compared with non–socially transitioned transgender historical control children.

Medically induced sexual transitioning

For pediatric and adolescent transsexual patients who express a desire to transition to the opposite sex, an Endocrine Society clinical practice guideline on endocrine treatment recommends that a mental health professional make the diagnosis of gender dysphoria. Then the medical provider needs to ensure that the patient understands the consequences of hormone suppression and cross-sex hormone therapy prior to beginning treatments. Only after early puberty has begun should gonadotropin-releasing hormone (GnRH) agonists be used to suppress pubertal hormones. At about age 16 years, cross-sex hormone treatments can begin, with surgery deferred at least until age 18 years if the patient desires full transitioning.

A Dutch study (Pediatrics. 2014 Oct. 134:696-704) showed that after gender reassignment, in young adulthood, gender dysphoria “was alleviated and psychological functioning had steadily improved. Well-being was similar to or better than same-age young adults from the general population.” No patients reported any regret during any stages of the sex-reassignment protocol.

There is some concern about adverse effects of the GnRH agonists, such as on bone mass and health, the brain, and fertility. But no detrimental effects were observed in a study on executive functioning, which undergoes significant development during puberty, in either male-to-female or female-to-male individuals.

Future parenthood may be an option if the patient is old enough. “We always encourage them to either freeze sperm, or we can potentially freeze eggs before embarking on phenotypic transition,” Dr. Rosenthal said. But allowing a patient to get to a stage of spermatogenesis or egg production would allow puberty to proceed to a significant degree. “So one of the exciting areas of research is actually taking prepubertal tissue … [in mice] they took neonatal testicular tissue and they basically showed you could take it all the way through the steps of full maturation and get progeny that were reproductively competent,” he said. Similar studies are being done in humans, mainly because there is interest in preserving fertility of children undergoing cancer treatments.

Barriers to care for transgender youth include limited access to medications, including off-label use, great expense, and insurance company denials of reimbursement. There are also relatively few clinical programs and a lack of training for health care professionals, as well as prejudice and misunderstanding, even among professionals.

ASCO Annual Meeting 2016
© ASCO/Matt Herp

CHICAGO—Nearly 60% of chronic myeloid leukemia (CML) patients who switch to nilotinib from imatinib maintain treatment-free remission for 48 weeks after stopping treatment, according to a new study, ENESTop, presented at the 2016 ASCO Annual Meeting (abstract 7054). 

Treatment-free remission (TFR)—stopping tyrosine kinase inhibitor therapy after achieving a sustained deep molecular response—is an emerging treatment goal for patients with CML in chronic phase (CML-CP).

Results from Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Complete Molecular Response (ENESTcmr) demonstrated that patients on long-term imatinib who had not achieved MR4.5 were more likely to achieve this response by switching to nilotinib than by remaining on imatinib. 

“This suggests that, compared with remaining on imatinib, switching to nilotinib may enable more of these patients to reach a molecular response level required for attempting to achieve TFR in clinical trials,” said lead author Timothy Hughes, MD, of University of Adelaide in Australia. 

ENESTop is the first study, providing the largest set of prospective TFR data to date, to specifically assess TFR in patients who achieved a sustained deep molecular response after switching from imatinib to nilotinib. 

The trial evaluated 126 patients who were able to achieve a sustained deep molecular response with nilotinib, but not with prior imatinib therapy.

The study met its primary endpoint of the proportion of patients without confirmed loss of MR4.0 or loss of major molecular response (MMR) within 48 weeks of nilotinib discontinuation in the TFR phase. 

Some 57.9% patients who achieved a sustained deep molecular response following at least three years of nilotinib therapy maintained a molecular response 48 weeks after stopping treatment.

Of the 51 patients with confirmed loss of MR4.0 or loss of MMR who restarted nilotinib, 98.0% regained at least MMR, with 94.1% regaining MR4.0 and 92.2% regaining MR4.5. 

By weeks 12 and 13 of treatment reinitiation with nilotinib, half of retreated patients already achieved MR4.0 and MR4.5, respectively. 

One patient entered the treatment reinitiation phase, but did not regain MMR by 20 weeks and discontinued the study. 

“MR4.5 achieved following the switch from imatinib to nilotinib,” Dr Hughes said, “was durable in most patients; more than three quarters of enrolled patients were eligible to enter the TFR phase.”

No new safety signals were observed, Dr Hughes said. Consistent with reports in imatinib-treated patients, the rates of all grade musculoskeletal pain were 42.1% in the first year of the TFR phase versus 14.3% while still taking nilotinib in the consolidation phase. 

Dr Hughes said the results suggest “TFR can be maintained in the majority of patients who achieve a sustained deep molecular response with nilotinib following switch from imatinib.”

He continued, “The results from ENESTop, together with those from ENESTcmr, show that a higher proportion of patients switching to nilotinib achieve MR 4.5, suggesting that a higher proportion of patients switching to nilotinib will achieve TFR compared with patients continuing on imatinib.”

Novartis is the sponsor of ENESTop and the manufacturer of imatinib (Gleevec) and nilotinib (Tasigna). Dr Hughes disclosed that he has received honoraria and research funding from Novartis.

ASCO Annual Meeting 2016
© ASCO/Matt Herp

CHICAGO—Nearly 60% of chronic myeloid leukemia (CML) patients who switch to nilotinib from imatinib maintain treatment-free remission for 48 weeks after stopping treatment, according to a new study, ENESTop, presented at the 2016 ASCO Annual Meeting (abstract 7054). 

Treatment-free remission (TFR)—stopping tyrosine kinase inhibitor therapy after achieving a sustained deep molecular response—is an emerging treatment goal for patients with CML in chronic phase (CML-CP).

Results from Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Complete Molecular Response (ENESTcmr) demonstrated that patients on long-term imatinib who had not achieved MR4.5 were more likely to achieve this response by switching to nilotinib than by remaining on imatinib. 

“This suggests that, compared with remaining on imatinib, switching to nilotinib may enable more of these patients to reach a molecular response level required for attempting to achieve TFR in clinical trials,” said lead author Timothy Hughes, MD, of University of Adelaide in Australia. 

ENESTop is the first study, providing the largest set of prospective TFR data to date, to specifically assess TFR in patients who achieved a sustained deep molecular response after switching from imatinib to nilotinib. 

The trial evaluated 126 patients who were able to achieve a sustained deep molecular response with nilotinib, but not with prior imatinib therapy.

The study met its primary endpoint of the proportion of patients without confirmed loss of MR4.0 or loss of major molecular response (MMR) within 48 weeks of nilotinib discontinuation in the TFR phase. 

Some 57.9% patients who achieved a sustained deep molecular response following at least three years of nilotinib therapy maintained a molecular response 48 weeks after stopping treatment.

Of the 51 patients with confirmed loss of MR4.0 or loss of MMR who restarted nilotinib, 98.0% regained at least MMR, with 94.1% regaining MR4.0 and 92.2% regaining MR4.5. 

By weeks 12 and 13 of treatment reinitiation with nilotinib, half of retreated patients already achieved MR4.0 and MR4.5, respectively. 

One patient entered the treatment reinitiation phase, but did not regain MMR by 20 weeks and discontinued the study. 

“MR4.5 achieved following the switch from imatinib to nilotinib,” Dr Hughes said, “was durable in most patients; more than three quarters of enrolled patients were eligible to enter the TFR phase.”

No new safety signals were observed, Dr Hughes said. Consistent with reports in imatinib-treated patients, the rates of all grade musculoskeletal pain were 42.1% in the first year of the TFR phase versus 14.3% while still taking nilotinib in the consolidation phase. 

Dr Hughes said the results suggest “TFR can be maintained in the majority of patients who achieve a sustained deep molecular response with nilotinib following switch from imatinib.”

He continued, “The results from ENESTop, together with those from ENESTcmr, show that a higher proportion of patients switching to nilotinib achieve MR 4.5, suggesting that a higher proportion of patients switching to nilotinib will achieve TFR compared with patients continuing on imatinib.”

Novartis is the sponsor of ENESTop and the manufacturer of imatinib (Gleevec) and nilotinib (Tasigna). Dr Hughes disclosed that he has received honoraria and research funding from Novartis.

ASCO Annual Meeting 2016
© ASCO/Matt Herp

CHICAGO—Nearly 60% of chronic myeloid leukemia (CML) patients who switch to nilotinib from imatinib maintain treatment-free remission for 48 weeks after stopping treatment, according to a new study, ENESTop, presented at the 2016 ASCO Annual Meeting (abstract 7054). 

Treatment-free remission (TFR)—stopping tyrosine kinase inhibitor therapy after achieving a sustained deep molecular response—is an emerging treatment goal for patients with CML in chronic phase (CML-CP).

Results from Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Complete Molecular Response (ENESTcmr) demonstrated that patients on long-term imatinib who had not achieved MR4.5 were more likely to achieve this response by switching to nilotinib than by remaining on imatinib. 

“This suggests that, compared with remaining on imatinib, switching to nilotinib may enable more of these patients to reach a molecular response level required for attempting to achieve TFR in clinical trials,” said lead author Timothy Hughes, MD, of University of Adelaide in Australia. 

ENESTop is the first study, providing the largest set of prospective TFR data to date, to specifically assess TFR in patients who achieved a sustained deep molecular response after switching from imatinib to nilotinib. 

The trial evaluated 126 patients who were able to achieve a sustained deep molecular response with nilotinib, but not with prior imatinib therapy.

The study met its primary endpoint of the proportion of patients without confirmed loss of MR4.0 or loss of major molecular response (MMR) within 48 weeks of nilotinib discontinuation in the TFR phase. 

Some 57.9% patients who achieved a sustained deep molecular response following at least three years of nilotinib therapy maintained a molecular response 48 weeks after stopping treatment.

Of the 51 patients with confirmed loss of MR4.0 or loss of MMR who restarted nilotinib, 98.0% regained at least MMR, with 94.1% regaining MR4.0 and 92.2% regaining MR4.5. 

By weeks 12 and 13 of treatment reinitiation with nilotinib, half of retreated patients already achieved MR4.0 and MR4.5, respectively. 

One patient entered the treatment reinitiation phase, but did not regain MMR by 20 weeks and discontinued the study. 

“MR4.5 achieved following the switch from imatinib to nilotinib,” Dr Hughes said, “was durable in most patients; more than three quarters of enrolled patients were eligible to enter the TFR phase.”

No new safety signals were observed, Dr Hughes said. Consistent with reports in imatinib-treated patients, the rates of all grade musculoskeletal pain were 42.1% in the first year of the TFR phase versus 14.3% while still taking nilotinib in the consolidation phase. 

Dr Hughes said the results suggest “TFR can be maintained in the majority of patients who achieve a sustained deep molecular response with nilotinib following switch from imatinib.”

He continued, “The results from ENESTop, together with those from ENESTcmr, show that a higher proportion of patients switching to nilotinib achieve MR 4.5, suggesting that a higher proportion of patients switching to nilotinib will achieve TFR compared with patients continuing on imatinib.”

Novartis is the sponsor of ENESTop and the manufacturer of imatinib (Gleevec) and nilotinib (Tasigna). Dr Hughes disclosed that he has received honoraria and research funding from Novartis.

Hagop M. Kantarjian, MD
Photo courtesy of MDACC

In multiple categories, the antibody-drug conjuagate inotuzumab ozogamicin achieved significantly better results than the standard of care in the treatment of adults with acute lymphoblastic leukemia (ALL). 

Patients in the inotuzumab arm experienced a higher rate of complete remissions, a greater frequency of achieving minimal residual disease negativity, and longer progression-free survival and overall survival. 

However, veno-occlusive liver disease occurred more frequently in the inotuzumab-treated patients. 

Inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, received breakthrough designation for ALL from the US Food and Drug Administration last October.

For this phase 3 trial, called INO-VATE, investigators randomized 326 patients to receive inotuzumab or the investigator’s choice of standard therapy. The first 218 patients, 109 in each arm, were included in the intent-to-treat analysis of complete remission.

Hagop M. Kantarjian, MD, of MD Anderson Cancer Center in Houston, Texas, presented the findings at the European Hematology Association meeting as abstract LB2233*. The study was simultaneously published in NEJM. Data cited here are based on the published paper.

Patients had to be 18 years of age or older and had to have relapsed or refractory disease with 5% or more blasts in the bone marrow. They had to be CD22-positive and could be either Philadelphia chromosome positive or negative. Patients had to be scheduled for their first or second salvage therapy. 

No cross-over between the groups was allowed.

The primary endpoints were complete remission including complete remission with incomplete hematologic recovery, and overall survival.

Treatments

Patients in the inotuzumab arm received the drug intravenously at a starting dose of 1.8 mg/m² per cycle for up to 6 cycles. Once a patient achieved complete remission or remission with incomplete hematologic recovery, the dose per cycle was reduced to 1.5 mg/m².

Patients in the standard therapy arm could receive one of three regimens: FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor), cytarabine plus mitoxantrone, or high-dose cytarabine. These regimens were chosen because they are commonly used for the treatment of relapsed or refractory ALL.

Patient characteristics

Patients in both arms were a median age of 47, range 18 – 79. And a little more than a third in each arm were 55 or older. Most patients were white, and about half had an ECOG performance status of 1.

Almost three quarters of the patients in each arm had bone marrow blasts of 50% or more.

Results

Patients in the inotuzumab arm received a median of 3 cycles of therapy and those in the standard therapy arm received a median of 1 cycle. 

More patients in the inotuzumab arm received treatment for 2 or more cycles (73%) compared to the standard therapy arm (22%), a finding the investigators said was expected.

Dose reductions were more common in the inotuzumab arm (12%) compared with the standard therapy arm (3%). 

More inotuzumab-treated patients discontinued therapy due to achieving complete remission (35%) than in the standard arm (15%).

And fewer patients in the inotuzumab arm (10%) discontinued treatment because of resistant disease than in the standard arm (40%).

Efficacy

The rate of complete remission, including incomplete hematologic recovery, was significantly higher in the inotuzumab group (80.7%) than in the standard group (29.4%), P<0.001.

In both groups, patients who achieved complete remission, including those with incomplete hematologic recovery, did so at the end of cycle 1. 

"Standard chemotherapy regimens result in complete remission in 31 to 41 percent of patients who relapse earlier,” Dr Kantarjian noted, “and just 18 to 25 percent in those who relapse later." 

"Patients in the inotuzumab ozogamicin study,” he continued, “had remission rates of 58% higher than previously reported, possibly due to patients being treated later in the disease course."

Among the complete responders, significantly more patients achieved minimal residual disease (MRD) negativity in the inotuzumab arm (78.4%) than in the standard therapy group (28.1%), P<0.001.

The median duration of remission was 4.6 months in the inotuzumab arm and 3.1 months in the standard therapy group, P=0.03.

And more patients treated with inotuzumab (41%) proceeded to stem cell transplant directly after treatment than in the standard therapy group (11%), P<0.001.

"Given that stem cell transplant is considered the only curative treatment option,” Dr Kantarjian said, “the ability of inotuzumab ozogamicin to increase the number of patients able to bridge to transplant is encouraging."

Survival

The intention-to-treat survival analysis included 164 patients in the inotuzumab arm and 162 in the standard therapy arm.

Progression-free survival (PFS) was significantly longer in the inotuzumab arm than in the standard therapy arm, a median of 5.0 months compared to 1.8 months, respectively, P<0.001.

The second primary objective of longer overall survival at the prespecified boundary of P=0.0208 was not met. Median overall survival was 7.7 months in the inotuzumab arm and 6.7 months in the standard therapy group, P=0.04.

Safety

In both treatment groups, the most common hematologic adverse events of any cause occurring during treatment were cytopenias.

Thrombocytopenia of grade 3 or higher was lower in the inotuzumab arm (37%) than in the standard therapy arm (59%).

Febrile neutropenia of grade 3 or higher occurred in 24% of inotuzumab-treated patients compared with 49% of patients in the standard therapy group. 

In the inotuzumab group, the most common non-hematologic adverse events of any grade included nausea (32%), headache (28%), and pyrexia (27%). Grade 3 or higher nausea, headache, and pyrexia occurred in 2%, 1%, and 4%, respectively.

In the standard therapy arm, the most common non-hematologic events of any grade included nausea (47%), pyrexia (43%), and diarrhea (40%). Grade 3 or higher nausea, pyrexia, and diarrhea occurred in 0%, 5%, and 1%, respectively. 

Febrile neutropenia was the most frequently reported serious adverse event, occurring in 12% of the inotuzumab-treated patients and 18% in the standard therapy group.

And liver-related adverse events were more common in the inotuzumab arm. 

The most frequent liver-related adverse event of any grade was increased aspartate aminotransferase level, 20% in the inotuzumab group and 10% in the standard therapy group, hyperbilirubinemia, 15% and 10%, respectively, and increased alanine aminotransferase level, 14% and 11%, respectively. 

Veno-occlusive liver disease (VOD) occurred more frequently with inotuzumab (11%, 15 patients) compared with standard therapy (1%, 1 patient). And cases were reported up to 2 years after randomization. 

Five of the 15 patients developed VOD during or shortly after inotuzumab treatment. No cases of VOD occurred during the administration of standard therapy. 

Seventeen deaths occurred during treatment in the inotuzumab arm and 11 in the standard therapy arm. Four deaths in the inotuzumab group and 2 in the standard therapy group were believed to be treatment-related. 

The study was funded by Pfizer.

*Data in the abstract differ from those published in NEJM.

Hagop M. Kantarjian, MD
Photo courtesy of MDACC

In multiple categories, the antibody-drug conjuagate inotuzumab ozogamicin achieved significantly better results than the standard of care in the treatment of adults with acute lymphoblastic leukemia (ALL). 

Patients in the inotuzumab arm experienced a higher rate of complete remissions, a greater frequency of achieving minimal residual disease negativity, and longer progression-free survival and overall survival. 

However, veno-occlusive liver disease occurred more frequently in the inotuzumab-treated patients. 

Inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, received breakthrough designation for ALL from the US Food and Drug Administration last October.

For this phase 3 trial, called INO-VATE, investigators randomized 326 patients to receive inotuzumab or the investigator’s choice of standard therapy. The first 218 patients, 109 in each arm, were included in the intent-to-treat analysis of complete remission.

Hagop M. Kantarjian, MD, of MD Anderson Cancer Center in Houston, Texas, presented the findings at the European Hematology Association meeting as abstract LB2233*. The study was simultaneously published in NEJM. Data cited here are based on the published paper.

Patients had to be 18 years of age or older and had to have relapsed or refractory disease with 5% or more blasts in the bone marrow. They had to be CD22-positive and could be either Philadelphia chromosome positive or negative. Patients had to be scheduled for their first or second salvage therapy. 

No cross-over between the groups was allowed.

The primary endpoints were complete remission including complete remission with incomplete hematologic recovery, and overall survival.

Treatments

Patients in the inotuzumab arm received the drug intravenously at a starting dose of 1.8 mg/m² per cycle for up to 6 cycles. Once a patient achieved complete remission or remission with incomplete hematologic recovery, the dose per cycle was reduced to 1.5 mg/m².

Patients in the standard therapy arm could receive one of three regimens: FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor), cytarabine plus mitoxantrone, or high-dose cytarabine. These regimens were chosen because they are commonly used for the treatment of relapsed or refractory ALL.

Patient characteristics

Patients in both arms were a median age of 47, range 18 – 79. And a little more than a third in each arm were 55 or older. Most patients were white, and about half had an ECOG performance status of 1.

Almost three quarters of the patients in each arm had bone marrow blasts of 50% or more.

Results

Patients in the inotuzumab arm received a median of 3 cycles of therapy and those in the standard therapy arm received a median of 1 cycle. 

More patients in the inotuzumab arm received treatment for 2 or more cycles (73%) compared to the standard therapy arm (22%), a finding the investigators said was expected.

Dose reductions were more common in the inotuzumab arm (12%) compared with the standard therapy arm (3%). 

More inotuzumab-treated patients discontinued therapy due to achieving complete remission (35%) than in the standard arm (15%).

And fewer patients in the inotuzumab arm (10%) discontinued treatment because of resistant disease than in the standard arm (40%).

Efficacy

The rate of complete remission, including incomplete hematologic recovery, was significantly higher in the inotuzumab group (80.7%) than in the standard group (29.4%), P<0.001.

In both groups, patients who achieved complete remission, including those with incomplete hematologic recovery, did so at the end of cycle 1. 

"Standard chemotherapy regimens result in complete remission in 31 to 41 percent of patients who relapse earlier,” Dr Kantarjian noted, “and just 18 to 25 percent in those who relapse later." 

"Patients in the inotuzumab ozogamicin study,” he continued, “had remission rates of 58% higher than previously reported, possibly due to patients being treated later in the disease course."

Among the complete responders, significantly more patients achieved minimal residual disease (MRD) negativity in the inotuzumab arm (78.4%) than in the standard therapy group (28.1%), P<0.001.

The median duration of remission was 4.6 months in the inotuzumab arm and 3.1 months in the standard therapy group, P=0.03.

And more patients treated with inotuzumab (41%) proceeded to stem cell transplant directly after treatment than in the standard therapy group (11%), P<0.001.

"Given that stem cell transplant is considered the only curative treatment option,” Dr Kantarjian said, “the ability of inotuzumab ozogamicin to increase the number of patients able to bridge to transplant is encouraging."

Survival

The intention-to-treat survival analysis included 164 patients in the inotuzumab arm and 162 in the standard therapy arm.

Progression-free survival (PFS) was significantly longer in the inotuzumab arm than in the standard therapy arm, a median of 5.0 months compared to 1.8 months, respectively, P<0.001.

The second primary objective of longer overall survival at the prespecified boundary of P=0.0208 was not met. Median overall survival was 7.7 months in the inotuzumab arm and 6.7 months in the standard therapy group, P=0.04.

Safety

In both treatment groups, the most common hematologic adverse events of any cause occurring during treatment were cytopenias.

Thrombocytopenia of grade 3 or higher was lower in the inotuzumab arm (37%) than in the standard therapy arm (59%).

Febrile neutropenia of grade 3 or higher occurred in 24% of inotuzumab-treated patients compared with 49% of patients in the standard therapy group. 

In the inotuzumab group, the most common non-hematologic adverse events of any grade included nausea (32%), headache (28%), and pyrexia (27%). Grade 3 or higher nausea, headache, and pyrexia occurred in 2%, 1%, and 4%, respectively.

In the standard therapy arm, the most common non-hematologic events of any grade included nausea (47%), pyrexia (43%), and diarrhea (40%). Grade 3 or higher nausea, pyrexia, and diarrhea occurred in 0%, 5%, and 1%, respectively. 

Febrile neutropenia was the most frequently reported serious adverse event, occurring in 12% of the inotuzumab-treated patients and 18% in the standard therapy group.

And liver-related adverse events were more common in the inotuzumab arm. 

The most frequent liver-related adverse event of any grade was increased aspartate aminotransferase level, 20% in the inotuzumab group and 10% in the standard therapy group, hyperbilirubinemia, 15% and 10%, respectively, and increased alanine aminotransferase level, 14% and 11%, respectively. 

Veno-occlusive liver disease (VOD) occurred more frequently with inotuzumab (11%, 15 patients) compared with standard therapy (1%, 1 patient). And cases were reported up to 2 years after randomization. 

Five of the 15 patients developed VOD during or shortly after inotuzumab treatment. No cases of VOD occurred during the administration of standard therapy. 

Seventeen deaths occurred during treatment in the inotuzumab arm and 11 in the standard therapy arm. Four deaths in the inotuzumab group and 2 in the standard therapy group were believed to be treatment-related. 

The study was funded by Pfizer.

*Data in the abstract differ from those published in NEJM.

Hagop M. Kantarjian, MD
Photo courtesy of MDACC

In multiple categories, the antibody-drug conjuagate inotuzumab ozogamicin achieved significantly better results than the standard of care in the treatment of adults with acute lymphoblastic leukemia (ALL). 

Patients in the inotuzumab arm experienced a higher rate of complete remissions, a greater frequency of achieving minimal residual disease negativity, and longer progression-free survival and overall survival. 

However, veno-occlusive liver disease occurred more frequently in the inotuzumab-treated patients. 

Inotuzumab ozogamicin, an anti-CD22 antibody conjugated to calicheamicin, received breakthrough designation for ALL from the US Food and Drug Administration last October.

For this phase 3 trial, called INO-VATE, investigators randomized 326 patients to receive inotuzumab or the investigator’s choice of standard therapy. The first 218 patients, 109 in each arm, were included in the intent-to-treat analysis of complete remission.

Hagop M. Kantarjian, MD, of MD Anderson Cancer Center in Houston, Texas, presented the findings at the European Hematology Association meeting as abstract LB2233*. The study was simultaneously published in NEJM. Data cited here are based on the published paper.

Patients had to be 18 years of age or older and had to have relapsed or refractory disease with 5% or more blasts in the bone marrow. They had to be CD22-positive and could be either Philadelphia chromosome positive or negative. Patients had to be scheduled for their first or second salvage therapy. 

No cross-over between the groups was allowed.

The primary endpoints were complete remission including complete remission with incomplete hematologic recovery, and overall survival.

Treatments

Patients in the inotuzumab arm received the drug intravenously at a starting dose of 1.8 mg/m² per cycle for up to 6 cycles. Once a patient achieved complete remission or remission with incomplete hematologic recovery, the dose per cycle was reduced to 1.5 mg/m².

Patients in the standard therapy arm could receive one of three regimens: FLAG (fludarabine, cytarabine, and granulocyte colony-stimulating factor), cytarabine plus mitoxantrone, or high-dose cytarabine. These regimens were chosen because they are commonly used for the treatment of relapsed or refractory ALL.

Patient characteristics

Patients in both arms were a median age of 47, range 18 – 79. And a little more than a third in each arm were 55 or older. Most patients were white, and about half had an ECOG performance status of 1.

Almost three quarters of the patients in each arm had bone marrow blasts of 50% or more.

Results

Patients in the inotuzumab arm received a median of 3 cycles of therapy and those in the standard therapy arm received a median of 1 cycle. 

More patients in the inotuzumab arm received treatment for 2 or more cycles (73%) compared to the standard therapy arm (22%), a finding the investigators said was expected.

Dose reductions were more common in the inotuzumab arm (12%) compared with the standard therapy arm (3%). 

More inotuzumab-treated patients discontinued therapy due to achieving complete remission (35%) than in the standard arm (15%).

And fewer patients in the inotuzumab arm (10%) discontinued treatment because of resistant disease than in the standard arm (40%).

Efficacy

The rate of complete remission, including incomplete hematologic recovery, was significantly higher in the inotuzumab group (80.7%) than in the standard group (29.4%), P<0.001.

In both groups, patients who achieved complete remission, including those with incomplete hematologic recovery, did so at the end of cycle 1. 

"Standard chemotherapy regimens result in complete remission in 31 to 41 percent of patients who relapse earlier,” Dr Kantarjian noted, “and just 18 to 25 percent in those who relapse later." 

"Patients in the inotuzumab ozogamicin study,” he continued, “had remission rates of 58% higher than previously reported, possibly due to patients being treated later in the disease course."

Among the complete responders, significantly more patients achieved minimal residual disease (MRD) negativity in the inotuzumab arm (78.4%) than in the standard therapy group (28.1%), P<0.001.

The median duration of remission was 4.6 months in the inotuzumab arm and 3.1 months in the standard therapy group, P=0.03.

And more patients treated with inotuzumab (41%) proceeded to stem cell transplant directly after treatment than in the standard therapy group (11%), P<0.001.

"Given that stem cell transplant is considered the only curative treatment option,” Dr Kantarjian said, “the ability of inotuzumab ozogamicin to increase the number of patients able to bridge to transplant is encouraging."

Survival

The intention-to-treat survival analysis included 164 patients in the inotuzumab arm and 162 in the standard therapy arm.

Progression-free survival (PFS) was significantly longer in the inotuzumab arm than in the standard therapy arm, a median of 5.0 months compared to 1.8 months, respectively, P<0.001.

The second primary objective of longer overall survival at the prespecified boundary of P=0.0208 was not met. Median overall survival was 7.7 months in the inotuzumab arm and 6.7 months in the standard therapy group, P=0.04.

Safety

In both treatment groups, the most common hematologic adverse events of any cause occurring during treatment were cytopenias.

Thrombocytopenia of grade 3 or higher was lower in the inotuzumab arm (37%) than in the standard therapy arm (59%).

Febrile neutropenia of grade 3 or higher occurred in 24% of inotuzumab-treated patients compared with 49% of patients in the standard therapy group. 

In the inotuzumab group, the most common non-hematologic adverse events of any grade included nausea (32%), headache (28%), and pyrexia (27%). Grade 3 or higher nausea, headache, and pyrexia occurred in 2%, 1%, and 4%, respectively.

In the standard therapy arm, the most common non-hematologic events of any grade included nausea (47%), pyrexia (43%), and diarrhea (40%). Grade 3 or higher nausea, pyrexia, and diarrhea occurred in 0%, 5%, and 1%, respectively. 

Febrile neutropenia was the most frequently reported serious adverse event, occurring in 12% of the inotuzumab-treated patients and 18% in the standard therapy group.

And liver-related adverse events were more common in the inotuzumab arm. 

The most frequent liver-related adverse event of any grade was increased aspartate aminotransferase level, 20% in the inotuzumab group and 10% in the standard therapy group, hyperbilirubinemia, 15% and 10%, respectively, and increased alanine aminotransferase level, 14% and 11%, respectively. 

Veno-occlusive liver disease (VOD) occurred more frequently with inotuzumab (11%, 15 patients) compared with standard therapy (1%, 1 patient). And cases were reported up to 2 years after randomization. 

Five of the 15 patients developed VOD during or shortly after inotuzumab treatment. No cases of VOD occurred during the administration of standard therapy. 

Seventeen deaths occurred during treatment in the inotuzumab arm and 11 in the standard therapy arm. Four deaths in the inotuzumab group and 2 in the standard therapy group were believed to be treatment-related. 

The study was funded by Pfizer.

*Data in the abstract differ from those published in NEJM.