SAN ANTONIO – Patients with HER2-positive early breast cancer with residual invasive disease following neoadjuvant therapy had a 50% reduction in risk for invasive breast cancer recurrence or death when they were treated with the antibody-drug conjugate trastuzumab emtansine (T-DM1; Kadcyla), results of the KATHERINE trial showed.

Among 743 patients randomized to adjuvant therapy with T-DM1, the 3-year invasive disease-free survival (IDFS) rate was 88.3%, compared with 77.0% for patients assigned to adjuvant trastuzumab (Herceptin).

The hazard ratio for IDFS – a composite endpoint of freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause – was 0.50 (P less than .001), reported Charles E. Geyer Jr., MD, from Virginia Commonwealth University, Richmond.

“While additional follow-up will be necessary to evaluate the effect of T-DM1 on overall survival, the compelling and consistent efficacy seen on the IDFS endpoint with the safety profile will likely form the foundation of a new standard of care in the KATHERINE patient population,” he said at the San Antonio Breast Cancer Symposium.

Results from KATHERINE were published online in the New England Journal of Medicine to coincide with its presentation in a briefing and in a general session.

KATHERINE was an open-label, phase 3 trial pitting T-DM1 against trastuzumab as adjuvant therapy in patients with early HER2-positive breast cancer with residual invasive disease in the breast or axilla at surgery following neoadjuvant therapy with a taxane (with or without an anthracycline) and trastuzumab. After stratification for clinical presentation (operable vs. inoperable), hormone receptor status, type of preoperative therapy, and pathological nodal status after neoadjuvant, patients were randomized to 14 cycles of either T-DM1 or trastuzumab.

The primary endpoint, IDFS, was as noted before. The trial was stopped after the results were found to cross the efficacy stopping boundary (HR less than 0.732) at the prespecified interim IDFS analysis in July 2018.

The efficacy of T-DM1 was supported by the finding that distant recurrence as the first invasive-disease event occurred in 10.5% of patients assigned to T-DM1, compared with 15.9% of those assigned to trastuzumab. The benefit of T-DM1 was consistent across all key subgroups, including all of the aforementioned stratification factors plus age, group, and race.

The safety analysis included data on 740 patients treated with T-DM1 and 720 treated with trastuzumab. The most common grade 3 or greater adverse events in the T-DM1 group included decreased platelet count in 5.7% and hypertension in 2.0%. The most common grade 3 or greater events in the trastuzumab group were hypertension in 1.2% and radiation-related skin injury in 1.0%.

Serious adverse events were more common in the T-DM1 arm, occurring in 12.7% of patients, compared with 8.1% in the trastuzumab arm. Adverse events leading to discontinuation of the trial drug occurred in 18.0% versus 2.1%, in the T-DM1 arm versus trastuzumab arm respectively.

Dr. Geyer said that, in general, adverse events in the T-DM1 arm were consistent with those seen in other studies, with manageable toxicities and no new safety signals.

“At the present time, the role of T-DM1 in the adjuvant and neoadjuvant setting is limited,” commented invited discussant Eric P. Winer, MD, from the Dana-Farber Cancer Institute in Boston. “It’s confined to patients who have residual disease after neoadjuvant therapy, but I predict this will change dramatically over time. Given how well tolerated T-DM1 is, how effective it was in this study, the answer that one comes to is why not consider using it more broadly and in an earlier-stage setting?”

Aditya Bardia, MD, from Massachusetts General Hospital in Boston, who was not involved in KATHERINE, agreed that the trial results are practice changing.

“I anticipate we would be using T-DM1 in the future for patients who would otherwise have been eligible for KATHERINE,” he said in an interview.

It’s still unclear, however, whether patients who receive pertuzumab (Perjeta) in the neoadjuvant setting and have residual lymph-node positive or estrogen receptor–negative might benefit with adjuvant therapy with T-DM1 instead of trastuzumab, he said.

“The second question that’s unclear at this time is patients who get 1 year of T-DM1, should they then receive neratinib [Nerlynx], because we have data from the ExteNET trial which showed that patients who complete 1 year of anti-HER2 therapy, if they receive 1 year of neratinib, there’s also reduced risk of recurrence, and that’s an unknown question at this time,” Dr. Bardia said.

The trial was funded by Hoffman–La Roche/Genentech. Dr. Geyer reported travel support from Roche and AstraZeneca, medical writing support from AbbVie and Roche, and honoraria from Celgene. Dr. Winer reported receiving grants for clinical research from and has served as an adviser or consultant to Genentech, AstraZeneca, Pfizer, and GlaxoSmithKline. Dr. Bardia reported relationships with Genentech and Novartis.

SOURCE: Geyer CE et al. N Engl J Med. 2018 Dec 5. doi: 10.1056/NEJMoa1814017.

SAN ANTONIO – Patients with HER2-positive early breast cancer with residual invasive disease following neoadjuvant therapy had a 50% reduction in risk for invasive breast cancer recurrence or death when they were treated with the antibody-drug conjugate trastuzumab emtansine (T-DM1; Kadcyla), results of the KATHERINE trial showed.

Among 743 patients randomized to adjuvant therapy with T-DM1, the 3-year invasive disease-free survival (IDFS) rate was 88.3%, compared with 77.0% for patients assigned to adjuvant trastuzumab (Herceptin).

The hazard ratio for IDFS – a composite endpoint of freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause – was 0.50 (P less than .001), reported Charles E. Geyer Jr., MD, from Virginia Commonwealth University, Richmond.

“While additional follow-up will be necessary to evaluate the effect of T-DM1 on overall survival, the compelling and consistent efficacy seen on the IDFS endpoint with the safety profile will likely form the foundation of a new standard of care in the KATHERINE patient population,” he said at the San Antonio Breast Cancer Symposium.

Results from KATHERINE were published online in the New England Journal of Medicine to coincide with its presentation in a briefing and in a general session.

KATHERINE was an open-label, phase 3 trial pitting T-DM1 against trastuzumab as adjuvant therapy in patients with early HER2-positive breast cancer with residual invasive disease in the breast or axilla at surgery following neoadjuvant therapy with a taxane (with or without an anthracycline) and trastuzumab. After stratification for clinical presentation (operable vs. inoperable), hormone receptor status, type of preoperative therapy, and pathological nodal status after neoadjuvant, patients were randomized to 14 cycles of either T-DM1 or trastuzumab.

The primary endpoint, IDFS, was as noted before. The trial was stopped after the results were found to cross the efficacy stopping boundary (HR less than 0.732) at the prespecified interim IDFS analysis in July 2018.

The efficacy of T-DM1 was supported by the finding that distant recurrence as the first invasive-disease event occurred in 10.5% of patients assigned to T-DM1, compared with 15.9% of those assigned to trastuzumab. The benefit of T-DM1 was consistent across all key subgroups, including all of the aforementioned stratification factors plus age, group, and race.

The safety analysis included data on 740 patients treated with T-DM1 and 720 treated with trastuzumab. The most common grade 3 or greater adverse events in the T-DM1 group included decreased platelet count in 5.7% and hypertension in 2.0%. The most common grade 3 or greater events in the trastuzumab group were hypertension in 1.2% and radiation-related skin injury in 1.0%.

Serious adverse events were more common in the T-DM1 arm, occurring in 12.7% of patients, compared with 8.1% in the trastuzumab arm. Adverse events leading to discontinuation of the trial drug occurred in 18.0% versus 2.1%, in the T-DM1 arm versus trastuzumab arm respectively.

Dr. Geyer said that, in general, adverse events in the T-DM1 arm were consistent with those seen in other studies, with manageable toxicities and no new safety signals.

“At the present time, the role of T-DM1 in the adjuvant and neoadjuvant setting is limited,” commented invited discussant Eric P. Winer, MD, from the Dana-Farber Cancer Institute in Boston. “It’s confined to patients who have residual disease after neoadjuvant therapy, but I predict this will change dramatically over time. Given how well tolerated T-DM1 is, how effective it was in this study, the answer that one comes to is why not consider using it more broadly and in an earlier-stage setting?”

Aditya Bardia, MD, from Massachusetts General Hospital in Boston, who was not involved in KATHERINE, agreed that the trial results are practice changing.

“I anticipate we would be using T-DM1 in the future for patients who would otherwise have been eligible for KATHERINE,” he said in an interview.

It’s still unclear, however, whether patients who receive pertuzumab (Perjeta) in the neoadjuvant setting and have residual lymph-node positive or estrogen receptor–negative might benefit with adjuvant therapy with T-DM1 instead of trastuzumab, he said.

“The second question that’s unclear at this time is patients who get 1 year of T-DM1, should they then receive neratinib [Nerlynx], because we have data from the ExteNET trial which showed that patients who complete 1 year of anti-HER2 therapy, if they receive 1 year of neratinib, there’s also reduced risk of recurrence, and that’s an unknown question at this time,” Dr. Bardia said.

The trial was funded by Hoffman–La Roche/Genentech. Dr. Geyer reported travel support from Roche and AstraZeneca, medical writing support from AbbVie and Roche, and honoraria from Celgene. Dr. Winer reported receiving grants for clinical research from and has served as an adviser or consultant to Genentech, AstraZeneca, Pfizer, and GlaxoSmithKline. Dr. Bardia reported relationships with Genentech and Novartis.

SOURCE: Geyer CE et al. N Engl J Med. 2018 Dec 5. doi: 10.1056/NEJMoa1814017.

SAN ANTONIO – Patients with HER2-positive early breast cancer with residual invasive disease following neoadjuvant therapy had a 50% reduction in risk for invasive breast cancer recurrence or death when they were treated with the antibody-drug conjugate trastuzumab emtansine (T-DM1; Kadcyla), results of the KATHERINE trial showed.

Among 743 patients randomized to adjuvant therapy with T-DM1, the 3-year invasive disease-free survival (IDFS) rate was 88.3%, compared with 77.0% for patients assigned to adjuvant trastuzumab (Herceptin).

The hazard ratio for IDFS – a composite endpoint of freedom from ipsilateral invasive breast tumor recurrence, ipsilateral locoregional invasive breast cancer recurrence, contralateral invasive breast cancer, distant recurrence, or death from any cause – was 0.50 (P less than .001), reported Charles E. Geyer Jr., MD, from Virginia Commonwealth University, Richmond.

“While additional follow-up will be necessary to evaluate the effect of T-DM1 on overall survival, the compelling and consistent efficacy seen on the IDFS endpoint with the safety profile will likely form the foundation of a new standard of care in the KATHERINE patient population,” he said at the San Antonio Breast Cancer Symposium.

Results from KATHERINE were published online in the New England Journal of Medicine to coincide with its presentation in a briefing and in a general session.

KATHERINE was an open-label, phase 3 trial pitting T-DM1 against trastuzumab as adjuvant therapy in patients with early HER2-positive breast cancer with residual invasive disease in the breast or axilla at surgery following neoadjuvant therapy with a taxane (with or without an anthracycline) and trastuzumab. After stratification for clinical presentation (operable vs. inoperable), hormone receptor status, type of preoperative therapy, and pathological nodal status after neoadjuvant, patients were randomized to 14 cycles of either T-DM1 or trastuzumab.

The primary endpoint, IDFS, was as noted before. The trial was stopped after the results were found to cross the efficacy stopping boundary (HR less than 0.732) at the prespecified interim IDFS analysis in July 2018.

The efficacy of T-DM1 was supported by the finding that distant recurrence as the first invasive-disease event occurred in 10.5% of patients assigned to T-DM1, compared with 15.9% of those assigned to trastuzumab. The benefit of T-DM1 was consistent across all key subgroups, including all of the aforementioned stratification factors plus age, group, and race.

The safety analysis included data on 740 patients treated with T-DM1 and 720 treated with trastuzumab. The most common grade 3 or greater adverse events in the T-DM1 group included decreased platelet count in 5.7% and hypertension in 2.0%. The most common grade 3 or greater events in the trastuzumab group were hypertension in 1.2% and radiation-related skin injury in 1.0%.

Serious adverse events were more common in the T-DM1 arm, occurring in 12.7% of patients, compared with 8.1% in the trastuzumab arm. Adverse events leading to discontinuation of the trial drug occurred in 18.0% versus 2.1%, in the T-DM1 arm versus trastuzumab arm respectively.

Dr. Geyer said that, in general, adverse events in the T-DM1 arm were consistent with those seen in other studies, with manageable toxicities and no new safety signals.

“At the present time, the role of T-DM1 in the adjuvant and neoadjuvant setting is limited,” commented invited discussant Eric P. Winer, MD, from the Dana-Farber Cancer Institute in Boston. “It’s confined to patients who have residual disease after neoadjuvant therapy, but I predict this will change dramatically over time. Given how well tolerated T-DM1 is, how effective it was in this study, the answer that one comes to is why not consider using it more broadly and in an earlier-stage setting?”

Aditya Bardia, MD, from Massachusetts General Hospital in Boston, who was not involved in KATHERINE, agreed that the trial results are practice changing.

“I anticipate we would be using T-DM1 in the future for patients who would otherwise have been eligible for KATHERINE,” he said in an interview.

It’s still unclear, however, whether patients who receive pertuzumab (Perjeta) in the neoadjuvant setting and have residual lymph-node positive or estrogen receptor–negative might benefit with adjuvant therapy with T-DM1 instead of trastuzumab, he said.

“The second question that’s unclear at this time is patients who get 1 year of T-DM1, should they then receive neratinib [Nerlynx], because we have data from the ExteNET trial which showed that patients who complete 1 year of anti-HER2 therapy, if they receive 1 year of neratinib, there’s also reduced risk of recurrence, and that’s an unknown question at this time,” Dr. Bardia said.

The trial was funded by Hoffman–La Roche/Genentech. Dr. Geyer reported travel support from Roche and AstraZeneca, medical writing support from AbbVie and Roche, and honoraria from Celgene. Dr. Winer reported receiving grants for clinical research from and has served as an adviser or consultant to Genentech, AstraZeneca, Pfizer, and GlaxoSmithKline. Dr. Bardia reported relationships with Genentech and Novartis.

SOURCE: Geyer CE et al. N Engl J Med. 2018 Dec 5. doi: 10.1056/NEJMoa1814017.

This is the final issue of The Journal of Community and Supportive Oncology. Since our launch – separately as the Journal of Supportive Oncology in 2003 and Community Oncology in 2004 – and through the 2014 merger to form JCSO, our purpose has always been to connect with practice-based caregivers and to provide them with carefully selected, peer-reviewed information that could easily be incorporated into daily practice. Our overarching goal was to help ensure the delivery of the best-possible care and outcomes for our patients. We hope we achieved that, and the results of a 2016 readership survey seemed to confirm as much. But from a business perspective, and especially with the transition to online publishing and intensely competitive advertising landscape, economic survival became increasingly elusive, and management decided to close the journal.

Looking ahead

From January 2019, JCSO’s sister publications, Hematology News and Oncology Practice, will reside on a shared digital platform, MDedge Oncology, that will focus on news and conference coverage. Archives for JCSO, JSO, and Community Oncology will be available on this new platform at www.mdedge.com/oncology after the launch. In addition, I will host a weekly podcast focusing on current trends and advances in clinical and supportive care. It will include a long-form interview with an expert in oncology, along the lines of the former JCSO Interview, and with short end-segments on patient care, translating new research to daily practice, and a monthly journal round-up. You'll be able to subscribe to and download it at Apple podcasts, using the search terms HemOnc and MDedge.
 

In this issue

We end with a bumper crop of articles, beginning with a report by Hedden and colleagues on page e234 describing how they developed, implemented, and evaluated a supportive care program for patients with prostate cancer. That is followed by a literature-based review article by Ibrahim colleagues detailing the effectiveness of duloxetine in the treatment of painful chemotherapy-induced peripheral neuropathy (p. e243). In the original research section, on page e250, Palmisiano and colleagues report on mortality outcomes in hospitalized patients with cancer after rapid response team activation; Jeurkar and colleagues compare risk models guiding growth factor use in chemotherapy (p. e256); and Chao and colleagues describe the symptom burdens associated with chemotherapy-induced anemia in patients with late-stage cancer (e260).

Challenging and elusive are the key words in this issue's Case Reports in which Pollock and colleagues describe the difficulties in managing a cetuximab rash (p. e272), Roberts and colleagues write about elevated liver function tests in a patient on palbociclib and fulvestrant (p. e277), and Mukherjee and colleagues describe a patient with intravascular large B-cell lymphoma, who presented both a diagnostic and management challenge for the care team (p. e280). Turn to page e283, where our regular contributor, Jane de Lartigue, has written an in-depth review on everything you need to know about biosimilars. Susan London follows up on page e290 with an article on findings from studies on biosimilars for 3 oncology drugs that were reported at this year’s annual meeting of the American Society of Clinical Oncology. Dr de Lartigue also reports on the approval of dabrafenib and trametinib for BRAF-mutant melanoma (e228) and osimertinib for advanced non–small-cell lung cancer (p. e231).

And finally…

I wish you and your colleagues and families all good things for the coming year. Thank you and goodbye – and stay in touch by downloading my podcast!

This is the final issue of The Journal of Community and Supportive Oncology. Since our launch – separately as the Journal of Supportive Oncology in 2003 and Community Oncology in 2004 – and through the 2014 merger to form JCSO, our purpose has always been to connect with practice-based caregivers and to provide them with carefully selected, peer-reviewed information that could easily be incorporated into daily practice. Our overarching goal was to help ensure the delivery of the best-possible care and outcomes for our patients. We hope we achieved that, and the results of a 2016 readership survey seemed to confirm as much. But from a business perspective, and especially with the transition to online publishing and intensely competitive advertising landscape, economic survival became increasingly elusive, and management decided to close the journal.

Looking ahead

From January 2019, JCSO’s sister publications, Hematology News and Oncology Practice, will reside on a shared digital platform, MDedge Oncology, that will focus on news and conference coverage. Archives for JCSO, JSO, and Community Oncology will be available on this new platform at www.mdedge.com/oncology after the launch. In addition, I will host a weekly podcast focusing on current trends and advances in clinical and supportive care. It will include a long-form interview with an expert in oncology, along the lines of the former JCSO Interview, and with short end-segments on patient care, translating new research to daily practice, and a monthly journal round-up. You'll be able to subscribe to and download it at Apple podcasts, using the search terms HemOnc and MDedge.
 

In this issue

We end with a bumper crop of articles, beginning with a report by Hedden and colleagues on page e234 describing how they developed, implemented, and evaluated a supportive care program for patients with prostate cancer. That is followed by a literature-based review article by Ibrahim colleagues detailing the effectiveness of duloxetine in the treatment of painful chemotherapy-induced peripheral neuropathy (p. e243). In the original research section, on page e250, Palmisiano and colleagues report on mortality outcomes in hospitalized patients with cancer after rapid response team activation; Jeurkar and colleagues compare risk models guiding growth factor use in chemotherapy (p. e256); and Chao and colleagues describe the symptom burdens associated with chemotherapy-induced anemia in patients with late-stage cancer (e260).

Challenging and elusive are the key words in this issue's Case Reports in which Pollock and colleagues describe the difficulties in managing a cetuximab rash (p. e272), Roberts and colleagues write about elevated liver function tests in a patient on palbociclib and fulvestrant (p. e277), and Mukherjee and colleagues describe a patient with intravascular large B-cell lymphoma, who presented both a diagnostic and management challenge for the care team (p. e280). Turn to page e283, where our regular contributor, Jane de Lartigue, has written an in-depth review on everything you need to know about biosimilars. Susan London follows up on page e290 with an article on findings from studies on biosimilars for 3 oncology drugs that were reported at this year’s annual meeting of the American Society of Clinical Oncology. Dr de Lartigue also reports on the approval of dabrafenib and trametinib for BRAF-mutant melanoma (e228) and osimertinib for advanced non–small-cell lung cancer (p. e231).

And finally…

I wish you and your colleagues and families all good things for the coming year. Thank you and goodbye – and stay in touch by downloading my podcast!

This is the final issue of The Journal of Community and Supportive Oncology. Since our launch – separately as the Journal of Supportive Oncology in 2003 and Community Oncology in 2004 – and through the 2014 merger to form JCSO, our purpose has always been to connect with practice-based caregivers and to provide them with carefully selected, peer-reviewed information that could easily be incorporated into daily practice. Our overarching goal was to help ensure the delivery of the best-possible care and outcomes for our patients. We hope we achieved that, and the results of a 2016 readership survey seemed to confirm as much. But from a business perspective, and especially with the transition to online publishing and intensely competitive advertising landscape, economic survival became increasingly elusive, and management decided to close the journal.

Looking ahead

From January 2019, JCSO’s sister publications, Hematology News and Oncology Practice, will reside on a shared digital platform, MDedge Oncology, that will focus on news and conference coverage. Archives for JCSO, JSO, and Community Oncology will be available on this new platform at www.mdedge.com/oncology after the launch. In addition, I will host a weekly podcast focusing on current trends and advances in clinical and supportive care. It will include a long-form interview with an expert in oncology, along the lines of the former JCSO Interview, and with short end-segments on patient care, translating new research to daily practice, and a monthly journal round-up. You'll be able to subscribe to and download it at Apple podcasts, using the search terms HemOnc and MDedge.
 

In this issue

We end with a bumper crop of articles, beginning with a report by Hedden and colleagues on page e234 describing how they developed, implemented, and evaluated a supportive care program for patients with prostate cancer. That is followed by a literature-based review article by Ibrahim colleagues detailing the effectiveness of duloxetine in the treatment of painful chemotherapy-induced peripheral neuropathy (p. e243). In the original research section, on page e250, Palmisiano and colleagues report on mortality outcomes in hospitalized patients with cancer after rapid response team activation; Jeurkar and colleagues compare risk models guiding growth factor use in chemotherapy (p. e256); and Chao and colleagues describe the symptom burdens associated with chemotherapy-induced anemia in patients with late-stage cancer (e260).

Challenging and elusive are the key words in this issue's Case Reports in which Pollock and colleagues describe the difficulties in managing a cetuximab rash (p. e272), Roberts and colleagues write about elevated liver function tests in a patient on palbociclib and fulvestrant (p. e277), and Mukherjee and colleagues describe a patient with intravascular large B-cell lymphoma, who presented both a diagnostic and management challenge for the care team (p. e280). Turn to page e283, where our regular contributor, Jane de Lartigue, has written an in-depth review on everything you need to know about biosimilars. Susan London follows up on page e290 with an article on findings from studies on biosimilars for 3 oncology drugs that were reported at this year’s annual meeting of the American Society of Clinical Oncology. Dr de Lartigue also reports on the approval of dabrafenib and trametinib for BRAF-mutant melanoma (e228) and osimertinib for advanced non–small-cell lung cancer (p. e231).

And finally…

I wish you and your colleagues and families all good things for the coming year. Thank you and goodbye – and stay in touch by downloading my podcast!

It is that time of year when federal compliance officers, clinical ethicists, and staff counsels are flooded with queries about the legal and ethical acceptability of gifts. And no wonder, all the winter holidays often involve giving gifts. The simple and spontaneous acts of giving and receiving gifts become more complicated and deliberative in the federal health care system. Both legal rules and ethical values bear upon who can offer and accept what gift to whom upon what occasion and in what amount. The “Standards of Ethical Conduct for Employees of the Executive Branch” devotes 2 entire subparts to the subject of gifts.¹ We will examine a small section of the document that can become a big issue for federal practitioners during that holiday—gifts from patients.

First, veterans (patients) are “prohibited sources” in section 5 CFR §2635.203 (d).¹ And since VA employees are subject to restrictions on accepting gifts from sources outside the government, unless an exception applies, federal employees may not accept a gift because of their official position (eg, Federal Practitioner, editor-in-chief) or a gift from a patient (prohibited source; [5 CFR §2635.201]).

It might seem like this is going to be a very short column this month, as gifts from patients are forbidden. Yet, a Christmas card or homemade fudge isn’t really a gift, is it?
5 CFR §2635.203 (b) defines what is and is not a gift: For example, minor items of food or items like a thank-you card are specifically excluded in section (b) 1-10.

Is Christmas an exception or are just types of gifts excluded?
There are exceptions to the general regulation about accepting gifts from prohibited sources. Many staff will recall hearing about the “$20 rule,” which is actually the “$20-50” rule stating that a federal employee may accept a gift from a patient (prohibited source) if the value of said gift is under $20 and the employee does not accept more than $50 from any single source in a calendar year. §2635.204 lists the exceptions. However, starting in 2017, the regulations changed to require that federal employees also consider not just whether they could accept a gift but—ethically—they should take the gift even if it was permitted under the law. The Office of Government Ethics made this change because it wanted to emphasize the importance of considering not just how things are but how things appear to be. The regulations contain detailed descriptions of what employees should think about and stipulates that the decisions will not be further scrutinized (5 CFR §2635.201[b]).¹

Based on this new emphasis on appearances, ethically, no doctor or nurse should accept the keys to a new BMW from a patient who owns a luxury car dealership. But what about more prosaic and probable presents: the holiday cookies a single father made with his children for the nurse practitioner who has been his primary care practitioner for years; the birdhouse a Vietnam veteran made in her crafts class for the surgeon who removed her gallbladder; or even the store-bought but no less heartfelt tin of popcorn from an elderly veteran for the hospitalist who saw him through a rough bought of pneumonia?

Related: Happy Federal New Year

The rules about practitioners accepting patient gifts are rational and unambiguous: It is the values conflict surrounding patient gifts that is often emotion driven and muddled; it may be easier and safer to adopt the “just say no” policy. And yet, while this might seem the most unassailable position to avoid a conflict of interest, could this possibly be a more practitioner- than patient-centered standard? Authoritative sources in the ethics literature are equally divided and ambivalent on the question.^2,3 The American College of Physicians Ethics Manual states: “In deciding whether to accept a gift from a patient, the physician should consider the nature of the gift and its value to the patient, the potential implications for the patient-physician relationship of accepting or refusing it, and the patient’s probable intention and expectations.”⁴ A small gift as a token of appreciation is not ethically problematic. Favored treatment as a result of acceptance of any gift is problematic, undermines professionalism, and may interfere with objectivity in the care of the patient.⁴

Related: Am I My Brother’s/Sister’s Keeper?

Many an ethics commentator have cautioned, “beware of patients bearing gifts.”⁵ In making an ethical assessment of whether or not to accept the gift, a key question a practitioner needs to ask him or herself is about the patient’s motive. Even the patient may be unaware of the reasons behind their giving, and the wise practitioner will take a mindful moment to think about the context and timing of the gift and the nature of his or her relationship to the patient. Sadly, many of our patients are lonely especially at this family time of year and on some level may hope the gift will help slide the professional relationship toward a more personal one. Some patients may think a gift might earn them preferential treatment. Finally, a few patients may have a romantic or sexual attraction toward a clinician.

Often in the latter 2 cases, a pattern will develop that discloses the patient’s true intent. Very expensive gifts, monetary gifts, excessively personal gifts, or frequent gifts should alert the practitioner that more may be going on. A kind reminder to the patient that providing good care is the only reward needed may be sufficient. For practitioners whose ethical code does not permit them to accept gifts, then a genuine thank you and an explanation of the rules and/or values behind the refusal may be necessary. There are other times when the practitioner or a supervisor/advisor may need to reset the boundaries or even to transfer the patient to another practitioner. The norms in mental health care and psychotherapy are more stringent because of the intimacy of the relationship and the potential vulnerability of patients.⁶

For gifts that seem genuine and generous or cost a trivial amount, then there is an ethical argument to be made for accepting them with gratitude. In many cultures, hospitality is a tradition, and expressing appreciation a virtue, so when a practitioner refuses to graciously take a small gift, they risk offending the patient. Rejection of a gift can be seen as disrespectful and could cause a rupture in an otherwise sound practitioner-patient relationship. Other patients experience strong feelings of gratitude and admiration for their practitioners, stronger than most of us recognize. The ability for a patient to give their practitioner a holiday gift, particularly one they invested time and energy in creating or choosing, can enhance their sense of self-worth and individual agency. These gifts are not so much an attempt to diminish the professional power differential but to close the gap between 2 human beings in an unequal relationship that is yet one of shared decision making. All practitioners should be aware of the often underappreciated social power of a gift to influence decisions.

Related: Caring Under a Microscope

At the same time, clinicians can strive to be sensitively attuned to the reality that, sometimes the cookie is just a cookie so eat and enjoy, just remember to share with your group. External judgments are often cited as practical rules of thumb for determining the ethical acceptability of a gift: Would you want your mother, newspaper, or colleague to know you took the present? I prefer an internal moral compass that steers always to the true north of is accepting this gift really in the patient’s best interest?

It is that time of year when federal compliance officers, clinical ethicists, and staff counsels are flooded with queries about the legal and ethical acceptability of gifts. And no wonder, all the winter holidays often involve giving gifts. The simple and spontaneous acts of giving and receiving gifts become more complicated and deliberative in the federal health care system. Both legal rules and ethical values bear upon who can offer and accept what gift to whom upon what occasion and in what amount. The “Standards of Ethical Conduct for Employees of the Executive Branch” devotes 2 entire subparts to the subject of gifts.¹ We will examine a small section of the document that can become a big issue for federal practitioners during that holiday—gifts from patients.

First, veterans (patients) are “prohibited sources” in section 5 CFR §2635.203 (d).¹ And since VA employees are subject to restrictions on accepting gifts from sources outside the government, unless an exception applies, federal employees may not accept a gift because of their official position (eg, Federal Practitioner, editor-in-chief) or a gift from a patient (prohibited source; [5 CFR §2635.201]).

It might seem like this is going to be a very short column this month, as gifts from patients are forbidden. Yet, a Christmas card or homemade fudge isn’t really a gift, is it?
5 CFR §2635.203 (b) defines what is and is not a gift: For example, minor items of food or items like a thank-you card are specifically excluded in section (b) 1-10.

Is Christmas an exception or are just types of gifts excluded?
There are exceptions to the general regulation about accepting gifts from prohibited sources. Many staff will recall hearing about the “$20 rule,” which is actually the “$20-50” rule stating that a federal employee may accept a gift from a patient (prohibited source) if the value of said gift is under $20 and the employee does not accept more than $50 from any single source in a calendar year. §2635.204 lists the exceptions. However, starting in 2017, the regulations changed to require that federal employees also consider not just whether they could accept a gift but—ethically—they should take the gift even if it was permitted under the law. The Office of Government Ethics made this change because it wanted to emphasize the importance of considering not just how things are but how things appear to be. The regulations contain detailed descriptions of what employees should think about and stipulates that the decisions will not be further scrutinized (5 CFR §2635.201[b]).¹

Based on this new emphasis on appearances, ethically, no doctor or nurse should accept the keys to a new BMW from a patient who owns a luxury car dealership. But what about more prosaic and probable presents: the holiday cookies a single father made with his children for the nurse practitioner who has been his primary care practitioner for years; the birdhouse a Vietnam veteran made in her crafts class for the surgeon who removed her gallbladder; or even the store-bought but no less heartfelt tin of popcorn from an elderly veteran for the hospitalist who saw him through a rough bought of pneumonia?

Related: Happy Federal New Year

The rules about practitioners accepting patient gifts are rational and unambiguous: It is the values conflict surrounding patient gifts that is often emotion driven and muddled; it may be easier and safer to adopt the “just say no” policy. And yet, while this might seem the most unassailable position to avoid a conflict of interest, could this possibly be a more practitioner- than patient-centered standard? Authoritative sources in the ethics literature are equally divided and ambivalent on the question.^2,3 The American College of Physicians Ethics Manual states: “In deciding whether to accept a gift from a patient, the physician should consider the nature of the gift and its value to the patient, the potential implications for the patient-physician relationship of accepting or refusing it, and the patient’s probable intention and expectations.”⁴ A small gift as a token of appreciation is not ethically problematic. Favored treatment as a result of acceptance of any gift is problematic, undermines professionalism, and may interfere with objectivity in the care of the patient.⁴

Related: Am I My Brother’s/Sister’s Keeper?

Many an ethics commentator have cautioned, “beware of patients bearing gifts.”⁵ In making an ethical assessment of whether or not to accept the gift, a key question a practitioner needs to ask him or herself is about the patient’s motive. Even the patient may be unaware of the reasons behind their giving, and the wise practitioner will take a mindful moment to think about the context and timing of the gift and the nature of his or her relationship to the patient. Sadly, many of our patients are lonely especially at this family time of year and on some level may hope the gift will help slide the professional relationship toward a more personal one. Some patients may think a gift might earn them preferential treatment. Finally, a few patients may have a romantic or sexual attraction toward a clinician.

Often in the latter 2 cases, a pattern will develop that discloses the patient’s true intent. Very expensive gifts, monetary gifts, excessively personal gifts, or frequent gifts should alert the practitioner that more may be going on. A kind reminder to the patient that providing good care is the only reward needed may be sufficient. For practitioners whose ethical code does not permit them to accept gifts, then a genuine thank you and an explanation of the rules and/or values behind the refusal may be necessary. There are other times when the practitioner or a supervisor/advisor may need to reset the boundaries or even to transfer the patient to another practitioner. The norms in mental health care and psychotherapy are more stringent because of the intimacy of the relationship and the potential vulnerability of patients.⁶

For gifts that seem genuine and generous or cost a trivial amount, then there is an ethical argument to be made for accepting them with gratitude. In many cultures, hospitality is a tradition, and expressing appreciation a virtue, so when a practitioner refuses to graciously take a small gift, they risk offending the patient. Rejection of a gift can be seen as disrespectful and could cause a rupture in an otherwise sound practitioner-patient relationship. Other patients experience strong feelings of gratitude and admiration for their practitioners, stronger than most of us recognize. The ability for a patient to give their practitioner a holiday gift, particularly one they invested time and energy in creating or choosing, can enhance their sense of self-worth and individual agency. These gifts are not so much an attempt to diminish the professional power differential but to close the gap between 2 human beings in an unequal relationship that is yet one of shared decision making. All practitioners should be aware of the often underappreciated social power of a gift to influence decisions.

Related: Caring Under a Microscope

At the same time, clinicians can strive to be sensitively attuned to the reality that, sometimes the cookie is just a cookie so eat and enjoy, just remember to share with your group. External judgments are often cited as practical rules of thumb for determining the ethical acceptability of a gift: Would you want your mother, newspaper, or colleague to know you took the present? I prefer an internal moral compass that steers always to the true north of is accepting this gift really in the patient’s best interest?

It is that time of year when federal compliance officers, clinical ethicists, and staff counsels are flooded with queries about the legal and ethical acceptability of gifts. And no wonder, all the winter holidays often involve giving gifts. The simple and spontaneous acts of giving and receiving gifts become more complicated and deliberative in the federal health care system. Both legal rules and ethical values bear upon who can offer and accept what gift to whom upon what occasion and in what amount. The “Standards of Ethical Conduct for Employees of the Executive Branch” devotes 2 entire subparts to the subject of gifts.¹ We will examine a small section of the document that can become a big issue for federal practitioners during that holiday—gifts from patients.

First, veterans (patients) are “prohibited sources” in section 5 CFR §2635.203 (d).¹ And since VA employees are subject to restrictions on accepting gifts from sources outside the government, unless an exception applies, federal employees may not accept a gift because of their official position (eg, Federal Practitioner, editor-in-chief) or a gift from a patient (prohibited source; [5 CFR §2635.201]).

It might seem like this is going to be a very short column this month, as gifts from patients are forbidden. Yet, a Christmas card or homemade fudge isn’t really a gift, is it?
5 CFR §2635.203 (b) defines what is and is not a gift: For example, minor items of food or items like a thank-you card are specifically excluded in section (b) 1-10.

Is Christmas an exception or are just types of gifts excluded?
There are exceptions to the general regulation about accepting gifts from prohibited sources. Many staff will recall hearing about the “$20 rule,” which is actually the “$20-50” rule stating that a federal employee may accept a gift from a patient (prohibited source) if the value of said gift is under $20 and the employee does not accept more than $50 from any single source in a calendar year. §2635.204 lists the exceptions. However, starting in 2017, the regulations changed to require that federal employees also consider not just whether they could accept a gift but—ethically—they should take the gift even if it was permitted under the law. The Office of Government Ethics made this change because it wanted to emphasize the importance of considering not just how things are but how things appear to be. The regulations contain detailed descriptions of what employees should think about and stipulates that the decisions will not be further scrutinized (5 CFR §2635.201[b]).¹

Based on this new emphasis on appearances, ethically, no doctor or nurse should accept the keys to a new BMW from a patient who owns a luxury car dealership. But what about more prosaic and probable presents: the holiday cookies a single father made with his children for the nurse practitioner who has been his primary care practitioner for years; the birdhouse a Vietnam veteran made in her crafts class for the surgeon who removed her gallbladder; or even the store-bought but no less heartfelt tin of popcorn from an elderly veteran for the hospitalist who saw him through a rough bought of pneumonia?

Related: Happy Federal New Year

The rules about practitioners accepting patient gifts are rational and unambiguous: It is the values conflict surrounding patient gifts that is often emotion driven and muddled; it may be easier and safer to adopt the “just say no” policy. And yet, while this might seem the most unassailable position to avoid a conflict of interest, could this possibly be a more practitioner- than patient-centered standard? Authoritative sources in the ethics literature are equally divided and ambivalent on the question.^2,3 The American College of Physicians Ethics Manual states: “In deciding whether to accept a gift from a patient, the physician should consider the nature of the gift and its value to the patient, the potential implications for the patient-physician relationship of accepting or refusing it, and the patient’s probable intention and expectations.”⁴ A small gift as a token of appreciation is not ethically problematic. Favored treatment as a result of acceptance of any gift is problematic, undermines professionalism, and may interfere with objectivity in the care of the patient.⁴

Related: Am I My Brother’s/Sister’s Keeper?

Many an ethics commentator have cautioned, “beware of patients bearing gifts.”⁵ In making an ethical assessment of whether or not to accept the gift, a key question a practitioner needs to ask him or herself is about the patient’s motive. Even the patient may be unaware of the reasons behind their giving, and the wise practitioner will take a mindful moment to think about the context and timing of the gift and the nature of his or her relationship to the patient. Sadly, many of our patients are lonely especially at this family time of year and on some level may hope the gift will help slide the professional relationship toward a more personal one. Some patients may think a gift might earn them preferential treatment. Finally, a few patients may have a romantic or sexual attraction toward a clinician.

Often in the latter 2 cases, a pattern will develop that discloses the patient’s true intent. Very expensive gifts, monetary gifts, excessively personal gifts, or frequent gifts should alert the practitioner that more may be going on. A kind reminder to the patient that providing good care is the only reward needed may be sufficient. For practitioners whose ethical code does not permit them to accept gifts, then a genuine thank you and an explanation of the rules and/or values behind the refusal may be necessary. There are other times when the practitioner or a supervisor/advisor may need to reset the boundaries or even to transfer the patient to another practitioner. The norms in mental health care and psychotherapy are more stringent because of the intimacy of the relationship and the potential vulnerability of patients.⁶

For gifts that seem genuine and generous or cost a trivial amount, then there is an ethical argument to be made for accepting them with gratitude. In many cultures, hospitality is a tradition, and expressing appreciation a virtue, so when a practitioner refuses to graciously take a small gift, they risk offending the patient. Rejection of a gift can be seen as disrespectful and could cause a rupture in an otherwise sound practitioner-patient relationship. Other patients experience strong feelings of gratitude and admiration for their practitioners, stronger than most of us recognize. The ability for a patient to give their practitioner a holiday gift, particularly one they invested time and energy in creating or choosing, can enhance their sense of self-worth and individual agency. These gifts are not so much an attempt to diminish the professional power differential but to close the gap between 2 human beings in an unequal relationship that is yet one of shared decision making. All practitioners should be aware of the often underappreciated social power of a gift to influence decisions.

Related: Caring Under a Microscope

At the same time, clinicians can strive to be sensitively attuned to the reality that, sometimes the cookie is just a cookie so eat and enjoy, just remember to share with your group. External judgments are often cited as practical rules of thumb for determining the ethical acceptability of a gift: Would you want your mother, newspaper, or colleague to know you took the present? I prefer an internal moral compass that steers always to the true north of is accepting this gift really in the patient’s best interest?

Dienogest as an option for endometriosis pain

For treatment of endometriosis-related pain, what about the drug dienogest and the cyclic oral contraceptive Qlaira, which contains dienogest?

Chow Kah Kiong, MBBS
Singapore

-- 

--

Norethindrone’s conversion to ethinyl estradiol

Dr. Barbieri’s editorial on the medical treatment of endometriosis is excellent! Does norethindrone acetate metabolize to ethinyl estradiol in a higher percentage when the dose is higher, or is it still 1%? We were taught that at doses of greater than 15 mg daily, norethindrone can contribute significant amounts of estrogen.

Lauren Barnes, MD
Albuquerque, New Mexico

Endometriosis is a surgical, not a medical, disease

I read with some dismay Dr. Barbieri’s editorial on medical treatment of endometriosis. As a long-time disciple of the eminent Dr. David Redwine, I have dedicated my practice focus over the past 28 years to minimally invasive curative solutions to many gynecologic problems. The data on the histology, qualitative hormonal differences, and inconsistent and poor long-term response of endometriosis to traditional hormonal suppressive therapies falls strongly in favor of complete and thorough laparoscopic excision—not “biopsy”—as the only truly curative treatment, certainly not medical therapy. Endometriosis is a surgical disease. The experience of the dedicated few in our field who have taken the time and effort to become experts in excision (not ablation) of endometriosis bears this out.

The tragedy is that the only Current Procedural Terminology code that is usable for reimbursement is 58662. Sadly, this code was assigned a resource-based relative value scale “value” many years ago, when the operation consisted of putting a scope in the abdomen and taking a sampling biopsy (which took all of 10 minutes). Of course, we know that a prolonged, delicate procedure requiring retroperitoneal dissection, ureterolysis, excision of deeply infiltrating rectovaginal septum endometriosis, and discoid or segmental bowel resection requires the kind of surgical expertise developed only by those who put in the time and effort to get good at this type of surgery. The majority of ObGyns who have a full obstetric practice and low surgical volumes simply are not going to struggle in the operating room over the many cases that it takes to become good, and safe, at this procedure only to receive an insulting reimbursement.

It is emblematic of this travesty that many of the best minimally invasive surgery practitioners do not accept insurance or other thirdparty payment such as Medicaid as they would otherwise not cover their overhead.

Putting premenopausal women into a severely hypoestrogenic state with medication is cruel and, even worse, does not cure the disease.

Balanced information on surgical management should have been presented in the article. And physicians who are not capable of proper laparoscopic excision should refer the patient.

Hugo Ribot, MD
Cartersville, Georgia

Continue to: Dr. Barbieri responds

I thank Drs. Chow, Barnes, and Ribot for their interest in my recent editorial on the medical treatment of endometriosis. I agree with Dr. Chow that dienogest, a synthetic progestin, is effective in the treatment of pelvic pain caused by endometriosis. In one observational study, norethindrone acetate 2.5 mg daily and dienogest 2 mg daily had similar efficacy in the treatment of pelvic pain. Dienogest treatment was associated with fewer side effects but was much more expensive than norethindrone acetate.¹ The US Food and Drug Administration has approved a combination estradiol- progestin pill (Natazia, Qlaira) as a contraceptive, and I have occasionally used this medication in my practice for women with pelvic pain caused by endometriosis. Dienogest monotherapy is not available in the United States.

Dr. Barnes reminds us that norethindrone is a substrate for the aromatase enzyme system and can be converted to ethinyl estradiol.² The conversion occurs at a very low rate, likely less than 0.4%.³ At a norethindrone acetate dose of 5 mg daily, aromatization would result in the production of less than 2 μg of ethinyl estradiol daily.

Dr. Ribot advocates for surgery as the primary treatment of pelvic pain caused by endometriosis. I agree with Dr. Ribot that, for severe pain caused by deep infiltrating endometriosis, surgery is an optimal approach. However, for women with pelvic pain and Stage I endometriosis, hormonal treatment after initial surgical diagnosis and treatment reduces pain recurrence and repetitive surgical procedures.⁴

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Dienogest as an option for endometriosis pain

For treatment of endometriosis-related pain, what about the drug dienogest and the cyclic oral contraceptive Qlaira, which contains dienogest?

Chow Kah Kiong, MBBS
Singapore

-- 

--

Norethindrone’s conversion to ethinyl estradiol

Dr. Barbieri’s editorial on the medical treatment of endometriosis is excellent! Does norethindrone acetate metabolize to ethinyl estradiol in a higher percentage when the dose is higher, or is it still 1%? We were taught that at doses of greater than 15 mg daily, norethindrone can contribute significant amounts of estrogen.

Lauren Barnes, MD
Albuquerque, New Mexico

Endometriosis is a surgical, not a medical, disease

I read with some dismay Dr. Barbieri’s editorial on medical treatment of endometriosis. As a long-time disciple of the eminent Dr. David Redwine, I have dedicated my practice focus over the past 28 years to minimally invasive curative solutions to many gynecologic problems. The data on the histology, qualitative hormonal differences, and inconsistent and poor long-term response of endometriosis to traditional hormonal suppressive therapies falls strongly in favor of complete and thorough laparoscopic excision—not “biopsy”—as the only truly curative treatment, certainly not medical therapy. Endometriosis is a surgical disease. The experience of the dedicated few in our field who have taken the time and effort to become experts in excision (not ablation) of endometriosis bears this out.

The tragedy is that the only Current Procedural Terminology code that is usable for reimbursement is 58662. Sadly, this code was assigned a resource-based relative value scale “value” many years ago, when the operation consisted of putting a scope in the abdomen and taking a sampling biopsy (which took all of 10 minutes). Of course, we know that a prolonged, delicate procedure requiring retroperitoneal dissection, ureterolysis, excision of deeply infiltrating rectovaginal septum endometriosis, and discoid or segmental bowel resection requires the kind of surgical expertise developed only by those who put in the time and effort to get good at this type of surgery. The majority of ObGyns who have a full obstetric practice and low surgical volumes simply are not going to struggle in the operating room over the many cases that it takes to become good, and safe, at this procedure only to receive an insulting reimbursement.

It is emblematic of this travesty that many of the best minimally invasive surgery practitioners do not accept insurance or other thirdparty payment such as Medicaid as they would otherwise not cover their overhead.

Putting premenopausal women into a severely hypoestrogenic state with medication is cruel and, even worse, does not cure the disease.

Balanced information on surgical management should have been presented in the article. And physicians who are not capable of proper laparoscopic excision should refer the patient.

Hugo Ribot, MD
Cartersville, Georgia

Continue to: Dr. Barbieri responds

I thank Drs. Chow, Barnes, and Ribot for their interest in my recent editorial on the medical treatment of endometriosis. I agree with Dr. Chow that dienogest, a synthetic progestin, is effective in the treatment of pelvic pain caused by endometriosis. In one observational study, norethindrone acetate 2.5 mg daily and dienogest 2 mg daily had similar efficacy in the treatment of pelvic pain. Dienogest treatment was associated with fewer side effects but was much more expensive than norethindrone acetate.¹ The US Food and Drug Administration has approved a combination estradiol- progestin pill (Natazia, Qlaira) as a contraceptive, and I have occasionally used this medication in my practice for women with pelvic pain caused by endometriosis. Dienogest monotherapy is not available in the United States.

Dr. Barnes reminds us that norethindrone is a substrate for the aromatase enzyme system and can be converted to ethinyl estradiol.² The conversion occurs at a very low rate, likely less than 0.4%.³ At a norethindrone acetate dose of 5 mg daily, aromatization would result in the production of less than 2 μg of ethinyl estradiol daily.

Dr. Ribot advocates for surgery as the primary treatment of pelvic pain caused by endometriosis. I agree with Dr. Ribot that, for severe pain caused by deep infiltrating endometriosis, surgery is an optimal approach. However, for women with pelvic pain and Stage I endometriosis, hormonal treatment after initial surgical diagnosis and treatment reduces pain recurrence and repetitive surgical procedures.⁴

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Dienogest as an option for endometriosis pain

For treatment of endometriosis-related pain, what about the drug dienogest and the cyclic oral contraceptive Qlaira, which contains dienogest?

Chow Kah Kiong, MBBS
Singapore

-- 

--

Norethindrone’s conversion to ethinyl estradiol

Dr. Barbieri’s editorial on the medical treatment of endometriosis is excellent! Does norethindrone acetate metabolize to ethinyl estradiol in a higher percentage when the dose is higher, or is it still 1%? We were taught that at doses of greater than 15 mg daily, norethindrone can contribute significant amounts of estrogen.

Lauren Barnes, MD
Albuquerque, New Mexico

Endometriosis is a surgical, not a medical, disease

I read with some dismay Dr. Barbieri’s editorial on medical treatment of endometriosis. As a long-time disciple of the eminent Dr. David Redwine, I have dedicated my practice focus over the past 28 years to minimally invasive curative solutions to many gynecologic problems. The data on the histology, qualitative hormonal differences, and inconsistent and poor long-term response of endometriosis to traditional hormonal suppressive therapies falls strongly in favor of complete and thorough laparoscopic excision—not “biopsy”—as the only truly curative treatment, certainly not medical therapy. Endometriosis is a surgical disease. The experience of the dedicated few in our field who have taken the time and effort to become experts in excision (not ablation) of endometriosis bears this out.

The tragedy is that the only Current Procedural Terminology code that is usable for reimbursement is 58662. Sadly, this code was assigned a resource-based relative value scale “value” many years ago, when the operation consisted of putting a scope in the abdomen and taking a sampling biopsy (which took all of 10 minutes). Of course, we know that a prolonged, delicate procedure requiring retroperitoneal dissection, ureterolysis, excision of deeply infiltrating rectovaginal septum endometriosis, and discoid or segmental bowel resection requires the kind of surgical expertise developed only by those who put in the time and effort to get good at this type of surgery. The majority of ObGyns who have a full obstetric practice and low surgical volumes simply are not going to struggle in the operating room over the many cases that it takes to become good, and safe, at this procedure only to receive an insulting reimbursement.

It is emblematic of this travesty that many of the best minimally invasive surgery practitioners do not accept insurance or other thirdparty payment such as Medicaid as they would otherwise not cover their overhead.

Putting premenopausal women into a severely hypoestrogenic state with medication is cruel and, even worse, does not cure the disease.

Balanced information on surgical management should have been presented in the article. And physicians who are not capable of proper laparoscopic excision should refer the patient.

Hugo Ribot, MD
Cartersville, Georgia

Continue to: Dr. Barbieri responds

I thank Drs. Chow, Barnes, and Ribot for their interest in my recent editorial on the medical treatment of endometriosis. I agree with Dr. Chow that dienogest, a synthetic progestin, is effective in the treatment of pelvic pain caused by endometriosis. In one observational study, norethindrone acetate 2.5 mg daily and dienogest 2 mg daily had similar efficacy in the treatment of pelvic pain. Dienogest treatment was associated with fewer side effects but was much more expensive than norethindrone acetate.¹ The US Food and Drug Administration has approved a combination estradiol- progestin pill (Natazia, Qlaira) as a contraceptive, and I have occasionally used this medication in my practice for women with pelvic pain caused by endometriosis. Dienogest monotherapy is not available in the United States.

Dr. Barnes reminds us that norethindrone is a substrate for the aromatase enzyme system and can be converted to ethinyl estradiol.² The conversion occurs at a very low rate, likely less than 0.4%.³ At a norethindrone acetate dose of 5 mg daily, aromatization would result in the production of less than 2 μg of ethinyl estradiol daily.

Dr. Ribot advocates for surgery as the primary treatment of pelvic pain caused by endometriosis. I agree with Dr. Ribot that, for severe pain caused by deep infiltrating endometriosis, surgery is an optimal approach. However, for women with pelvic pain and Stage I endometriosis, hormonal treatment after initial surgical diagnosis and treatment reduces pain recurrence and repetitive surgical procedures.⁴

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In the past decade, breastfeeding rates have increased substantially. Between 2000 and 2015, the proportion of infants who continued to breastfeed at 12 months increased from 16% to 36%. The proportion of infants who had any breastfeeding increased from 71% to 83%.¹ While the infant health benefits of breastfeeding are widely recognized, the maternal health benefits of breastfeeding are many and likely underappreciated.

Infant health benefits of breastfeeding

There are no large-scale, randomized studies of the long-term health benefits of breastfeeding versus formula feeding. The evidence supporting the health benefits of breastfeeding is derived from case-control and cohort studies. Breastfeeding directly benefits newborn and infant nutrition, gastrointestinal function, host defense, and psychological well-being. Compared with formula-fed newborns, breastfed infants have a reduced risk of infectious diseases including otitis media, gastroenteritis, respiratory infections, sudden infant death syndrome, and metabolic disease. These benefits alone strongly support the public health benefit of breastfeeding.² In addition, breastfeeding greatly benefits maternal health.

Maternal health benefits of breastfeeding

Breastfeeding reduces a woman’s risk for type 2 diabetes, hypertension, and coronary artery disease, myocardial infarction, as well as breast, ovarian, and endometrial cancer. There are few exposures that have such a multitude of positive health benefits.

filler 

Type 2 diabetes

In a prospective cohort study of 1,238 women without diabetes in 1985–1986, 182 women developed type 2 diabetes after 30 years of follow-up. Compared with never breastfeeding, breastfeeding for 0 to 6 months, >6 months to <12 months, or ≥12 months reduced the risk of type 2 diabetes by 25%, 48%, and 69% respectively.³ In the prospective Nurses’ Health Study, among parous women, each additional year of breastfeeding decreased the risk of type 2 diabetes by 15% compared with women who did not breastfeed.⁴

Hypertension

In the Women’s Health Initiative (WHI) study of postmenopausal women, a lifetime history of breastfeeding for 12 months or more was associated with a 12% decrease in the risk of hypertension.⁵ For parous women, the prevalence of hypertension among breastfeeding (≥12 months) and never breastfeeding women was estimated to be 38.6% versus 42.1%.⁵ Similar results were observed in the Nurses’ Health Study II.⁶

Myocardial infarction and coronary heart disease

In the prospective Nurses’ Health Study, during 1,350,965 person-years of follow-up, 2,540 women had a myocardial infarction (MI). Women who had breastfed for ≥ 2 years had a 37% decreased risk of MI compared with women who never breastfed. After adjustment for family history, lifestyle factors, and adiposity, the observed reduction in risk was 23%.⁷ In the WHI (observational study plus controlled trial), women with a single live birth who breastfed for 7 to 12 months had a lower risk of cardiovascular disease than women with a single live birth who did not breastfeed (hazard ratio, 0.72; 95% confidence interval, 0.53–97).⁵

Breast cancer

In a systematic review and meta-analysis of 100 publications, breastfeeding >12 months reduced the risk of breast cancer by 26%.⁸ In a systematic review of 47 studies, the relative risk of breast cancer decreased by 4.7% for every 12 months of breastfeeding.⁹ In a systematic review and meta-analysis of 3 studies, ever breastfeeding was associated with a 28% reduced risk for triple-negative (ER-, PR-, HER2-) breast cancer among parous women.¹⁰ Triple-negative breast cancer generally has a poorer prognosis than receptor-positive breast cancers.

Continue to: Ovarian Cancer

In a systematic review and meta-analysis of 40 publications, ever breastfeeding was associated with a 37% reduction in the risk of ovarian cancer.⁸ In a prospective study of 1.1 million women in the United Kingdom, 8,719 developed ovarian cancer. Among parous women, ovarian cancer risk was reduced by 10% for every 12 months of breastfeeding.¹¹

Endometrial cancer

In a meta-analysis of 17 publications, including 8,981 cases and 17,241 controls, ever breastfeeding was associated with an 11% reduction in breast cancer risk.¹² In a meta-analysis of 15 publications with 6,704 cases, breastfeeding was associated with a 26% reduction in endometrial cancer. After controlling for hormone use and body mass index, the reduced risk was in the range of 35%. A linear relationship between breastfeeding and reduced risk of endometrial cancer was observed, with 1 month of breastfeeding being associated with a 1.2% reduction in the risk of endometrial cancer.¹³

Let’s support our patients’ health by encouraging successful breastfeeding

Obstetrician-gynecologists play an important role in helping women make informed decisions about breastfeeding. Most professional organizations, including the American College of Obstetricians and Gynecologists, recommend exclusive breastfeeding for the first 6 months of life, with continued breastfeeding and introduction of complementary food from 6 to 12 months.^14,15 Birth practices that help to increase successful breastfeeding include:

• inform all pregnant women about the newborn and maternal health benefits and management of breastfeeding
• initiate skin-to-skin contact at birth
• encourage the initiation of breastfeeding within 1 hour of birth
• ensure that breastfeeding newborns do not receive any food or drink other than breast milk, unless medically indicated
• encourage breastfeeding women to not use pacifiers or artificial nipples.¹⁵

When women are discharged from the maternity center, providing information about community-based lactation support is helpful in ensuring continuation of successful breastfeeding.¹⁶

Most patients know that exercise and maintaining a healthy weight can reduce the risk of developing many prevalent diseases. However, far fewer patients know that breastfeeding can reduce the risk of developing type 2 diabetes, hypertension, and coronary artery disease, as well as breast, ovarian, and endometrial cancers. Educating our patients about these health benefits may help them to more fully commit to breastfeeding.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In the past decade, breastfeeding rates have increased substantially. Between 2000 and 2015, the proportion of infants who continued to breastfeed at 12 months increased from 16% to 36%. The proportion of infants who had any breastfeeding increased from 71% to 83%.¹ While the infant health benefits of breastfeeding are widely recognized, the maternal health benefits of breastfeeding are many and likely underappreciated.

Infant health benefits of breastfeeding

There are no large-scale, randomized studies of the long-term health benefits of breastfeeding versus formula feeding. The evidence supporting the health benefits of breastfeeding is derived from case-control and cohort studies. Breastfeeding directly benefits newborn and infant nutrition, gastrointestinal function, host defense, and psychological well-being. Compared with formula-fed newborns, breastfed infants have a reduced risk of infectious diseases including otitis media, gastroenteritis, respiratory infections, sudden infant death syndrome, and metabolic disease. These benefits alone strongly support the public health benefit of breastfeeding.² In addition, breastfeeding greatly benefits maternal health.

Maternal health benefits of breastfeeding

Breastfeeding reduces a woman’s risk for type 2 diabetes, hypertension, and coronary artery disease, myocardial infarction, as well as breast, ovarian, and endometrial cancer. There are few exposures that have such a multitude of positive health benefits.

filler 

Type 2 diabetes

In a prospective cohort study of 1,238 women without diabetes in 1985–1986, 182 women developed type 2 diabetes after 30 years of follow-up. Compared with never breastfeeding, breastfeeding for 0 to 6 months, >6 months to <12 months, or ≥12 months reduced the risk of type 2 diabetes by 25%, 48%, and 69% respectively.³ In the prospective Nurses’ Health Study, among parous women, each additional year of breastfeeding decreased the risk of type 2 diabetes by 15% compared with women who did not breastfeed.⁴

Hypertension

In the Women’s Health Initiative (WHI) study of postmenopausal women, a lifetime history of breastfeeding for 12 months or more was associated with a 12% decrease in the risk of hypertension.⁵ For parous women, the prevalence of hypertension among breastfeeding (≥12 months) and never breastfeeding women was estimated to be 38.6% versus 42.1%.⁵ Similar results were observed in the Nurses’ Health Study II.⁶

Myocardial infarction and coronary heart disease

In the prospective Nurses’ Health Study, during 1,350,965 person-years of follow-up, 2,540 women had a myocardial infarction (MI). Women who had breastfed for ≥ 2 years had a 37% decreased risk of MI compared with women who never breastfed. After adjustment for family history, lifestyle factors, and adiposity, the observed reduction in risk was 23%.⁷ In the WHI (observational study plus controlled trial), women with a single live birth who breastfed for 7 to 12 months had a lower risk of cardiovascular disease than women with a single live birth who did not breastfeed (hazard ratio, 0.72; 95% confidence interval, 0.53–97).⁵

Breast cancer

In a systematic review and meta-analysis of 100 publications, breastfeeding >12 months reduced the risk of breast cancer by 26%.⁸ In a systematic review of 47 studies, the relative risk of breast cancer decreased by 4.7% for every 12 months of breastfeeding.⁹ In a systematic review and meta-analysis of 3 studies, ever breastfeeding was associated with a 28% reduced risk for triple-negative (ER-, PR-, HER2-) breast cancer among parous women.¹⁰ Triple-negative breast cancer generally has a poorer prognosis than receptor-positive breast cancers.

Continue to: Ovarian Cancer

In a systematic review and meta-analysis of 40 publications, ever breastfeeding was associated with a 37% reduction in the risk of ovarian cancer.⁸ In a prospective study of 1.1 million women in the United Kingdom, 8,719 developed ovarian cancer. Among parous women, ovarian cancer risk was reduced by 10% for every 12 months of breastfeeding.¹¹

Endometrial cancer

In a meta-analysis of 17 publications, including 8,981 cases and 17,241 controls, ever breastfeeding was associated with an 11% reduction in breast cancer risk.¹² In a meta-analysis of 15 publications with 6,704 cases, breastfeeding was associated with a 26% reduction in endometrial cancer. After controlling for hormone use and body mass index, the reduced risk was in the range of 35%. A linear relationship between breastfeeding and reduced risk of endometrial cancer was observed, with 1 month of breastfeeding being associated with a 1.2% reduction in the risk of endometrial cancer.¹³

Let’s support our patients’ health by encouraging successful breastfeeding

Obstetrician-gynecologists play an important role in helping women make informed decisions about breastfeeding. Most professional organizations, including the American College of Obstetricians and Gynecologists, recommend exclusive breastfeeding for the first 6 months of life, with continued breastfeeding and introduction of complementary food from 6 to 12 months.^14,15 Birth practices that help to increase successful breastfeeding include:

• inform all pregnant women about the newborn and maternal health benefits and management of breastfeeding
• initiate skin-to-skin contact at birth
• encourage the initiation of breastfeeding within 1 hour of birth
• ensure that breastfeeding newborns do not receive any food or drink other than breast milk, unless medically indicated
• encourage breastfeeding women to not use pacifiers or artificial nipples.¹⁵

When women are discharged from the maternity center, providing information about community-based lactation support is helpful in ensuring continuation of successful breastfeeding.¹⁶

Most patients know that exercise and maintaining a healthy weight can reduce the risk of developing many prevalent diseases. However, far fewer patients know that breastfeeding can reduce the risk of developing type 2 diabetes, hypertension, and coronary artery disease, as well as breast, ovarian, and endometrial cancers. Educating our patients about these health benefits may help them to more fully commit to breastfeeding.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In the past decade, breastfeeding rates have increased substantially. Between 2000 and 2015, the proportion of infants who continued to breastfeed at 12 months increased from 16% to 36%. The proportion of infants who had any breastfeeding increased from 71% to 83%.¹ While the infant health benefits of breastfeeding are widely recognized, the maternal health benefits of breastfeeding are many and likely underappreciated.

Infant health benefits of breastfeeding

There are no large-scale, randomized studies of the long-term health benefits of breastfeeding versus formula feeding. The evidence supporting the health benefits of breastfeeding is derived from case-control and cohort studies. Breastfeeding directly benefits newborn and infant nutrition, gastrointestinal function, host defense, and psychological well-being. Compared with formula-fed newborns, breastfed infants have a reduced risk of infectious diseases including otitis media, gastroenteritis, respiratory infections, sudden infant death syndrome, and metabolic disease. These benefits alone strongly support the public health benefit of breastfeeding.² In addition, breastfeeding greatly benefits maternal health.

Maternal health benefits of breastfeeding

Breastfeeding reduces a woman’s risk for type 2 diabetes, hypertension, and coronary artery disease, myocardial infarction, as well as breast, ovarian, and endometrial cancer. There are few exposures that have such a multitude of positive health benefits.

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Type 2 diabetes

In a prospective cohort study of 1,238 women without diabetes in 1985–1986, 182 women developed type 2 diabetes after 30 years of follow-up. Compared with never breastfeeding, breastfeeding for 0 to 6 months, >6 months to <12 months, or ≥12 months reduced the risk of type 2 diabetes by 25%, 48%, and 69% respectively.³ In the prospective Nurses’ Health Study, among parous women, each additional year of breastfeeding decreased the risk of type 2 diabetes by 15% compared with women who did not breastfeed.⁴

Hypertension

In the Women’s Health Initiative (WHI) study of postmenopausal women, a lifetime history of breastfeeding for 12 months or more was associated with a 12% decrease in the risk of hypertension.⁵ For parous women, the prevalence of hypertension among breastfeeding (≥12 months) and never breastfeeding women was estimated to be 38.6% versus 42.1%.⁵ Similar results were observed in the Nurses’ Health Study II.⁶

Myocardial infarction and coronary heart disease

In the prospective Nurses’ Health Study, during 1,350,965 person-years of follow-up, 2,540 women had a myocardial infarction (MI). Women who had breastfed for ≥ 2 years had a 37% decreased risk of MI compared with women who never breastfed. After adjustment for family history, lifestyle factors, and adiposity, the observed reduction in risk was 23%.⁷ In the WHI (observational study plus controlled trial), women with a single live birth who breastfed for 7 to 12 months had a lower risk of cardiovascular disease than women with a single live birth who did not breastfeed (hazard ratio, 0.72; 95% confidence interval, 0.53–97).⁵

Breast cancer

In a systematic review and meta-analysis of 100 publications, breastfeeding >12 months reduced the risk of breast cancer by 26%.⁸ In a systematic review of 47 studies, the relative risk of breast cancer decreased by 4.7% for every 12 months of breastfeeding.⁹ In a systematic review and meta-analysis of 3 studies, ever breastfeeding was associated with a 28% reduced risk for triple-negative (ER-, PR-, HER2-) breast cancer among parous women.¹⁰ Triple-negative breast cancer generally has a poorer prognosis than receptor-positive breast cancers.

Continue to: Ovarian Cancer

In a systematic review and meta-analysis of 40 publications, ever breastfeeding was associated with a 37% reduction in the risk of ovarian cancer.⁸ In a prospective study of 1.1 million women in the United Kingdom, 8,719 developed ovarian cancer. Among parous women, ovarian cancer risk was reduced by 10% for every 12 months of breastfeeding.¹¹

Endometrial cancer

In a meta-analysis of 17 publications, including 8,981 cases and 17,241 controls, ever breastfeeding was associated with an 11% reduction in breast cancer risk.¹² In a meta-analysis of 15 publications with 6,704 cases, breastfeeding was associated with a 26% reduction in endometrial cancer. After controlling for hormone use and body mass index, the reduced risk was in the range of 35%. A linear relationship between breastfeeding and reduced risk of endometrial cancer was observed, with 1 month of breastfeeding being associated with a 1.2% reduction in the risk of endometrial cancer.¹³

Let’s support our patients’ health by encouraging successful breastfeeding

Obstetrician-gynecologists play an important role in helping women make informed decisions about breastfeeding. Most professional organizations, including the American College of Obstetricians and Gynecologists, recommend exclusive breastfeeding for the first 6 months of life, with continued breastfeeding and introduction of complementary food from 6 to 12 months.^14,15 Birth practices that help to increase successful breastfeeding include:

• inform all pregnant women about the newborn and maternal health benefits and management of breastfeeding
• initiate skin-to-skin contact at birth
• encourage the initiation of breastfeeding within 1 hour of birth
• ensure that breastfeeding newborns do not receive any food or drink other than breast milk, unless medically indicated
• encourage breastfeeding women to not use pacifiers or artificial nipples.¹⁵

When women are discharged from the maternity center, providing information about community-based lactation support is helpful in ensuring continuation of successful breastfeeding.¹⁶

Most patients know that exercise and maintaining a healthy weight can reduce the risk of developing many prevalent diseases. However, far fewer patients know that breastfeeding can reduce the risk of developing type 2 diabetes, hypertension, and coronary artery disease, as well as breast, ovarian, and endometrial cancers. Educating our patients about these health benefits may help them to more fully commit to breastfeeding.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

There was no significant difference in mortality between critically ill patients who received pantoprazole prophylaxis for gastrointestinal bleeding, and those who received placebo, new findings suggest.

In a multicenter, randomized trial of 3,298 adult patients at risk for gastrointestinal bleeding, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died at 90 days (relative risk, 1.02; 95% confidence interval, 0.91-1.13; P = .76). The results were published in the New England Journal of Medicine.

Patients were aged 18 years or older; had been admitted to the ICU for an acute condition in one of six international centers; and had at least one risk factor for gastrointestinal bleeding including shock, use of anticoagulant agents, renal replacement therapy, mechanical ventilation (expected to last more than 24 hours), any history of liver disease, or any history of or ongoing coagulopathy. A total of 1,645 patients were randomly assigned to receive 40 mg of intravenous pantoprazole once daily and 1,653 received placebo, reported Mette Krag, MD, of the department of intensive care at Rigshospitalet in Copenhagen, and her coauthors.

The primary outcome was 90-day mortality. Secondary outcomes were clinically important events in the ICU, clinically important gastrointestinal bleeding in the ICU, infectious adverse events in the ICU, and days alive without the use of life support within the 90-day period.

One or more clinically important events occurred in 21.9% of patients in the pantoprazole group and in 22.6% in the placebo group (RR, 0.96; 95% CI, 0.83-1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, compared with 4.2% in the placebo group, Dr. Krag and her coauthors wrote.

The findings are similar to other recently published results, which showed “no significant differences ... in the rates of death or infectious complications between patients receiving placebo or no prophylaxis and those receiving proton pump inhibitors,” the authors wrote.

Dr. Krag reported financial support from Innovation Fund Denmark, Ehrenreich’s Foundation, and several other organizations.

SOURCE: Krag M et al. N Engl J Med. 2018 Dec 6. doi: 10.1056/NEJMoa1714919.

This article was updated 12/6/18.

There was no significant difference in mortality between critically ill patients who received pantoprazole prophylaxis for gastrointestinal bleeding, and those who received placebo, new findings suggest.

In a multicenter, randomized trial of 3,298 adult patients at risk for gastrointestinal bleeding, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died at 90 days (relative risk, 1.02; 95% confidence interval, 0.91-1.13; P = .76). The results were published in the New England Journal of Medicine.

Patients were aged 18 years or older; had been admitted to the ICU for an acute condition in one of six international centers; and had at least one risk factor for gastrointestinal bleeding including shock, use of anticoagulant agents, renal replacement therapy, mechanical ventilation (expected to last more than 24 hours), any history of liver disease, or any history of or ongoing coagulopathy. A total of 1,645 patients were randomly assigned to receive 40 mg of intravenous pantoprazole once daily and 1,653 received placebo, reported Mette Krag, MD, of the department of intensive care at Rigshospitalet in Copenhagen, and her coauthors.

The primary outcome was 90-day mortality. Secondary outcomes were clinically important events in the ICU, clinically important gastrointestinal bleeding in the ICU, infectious adverse events in the ICU, and days alive without the use of life support within the 90-day period.

One or more clinically important events occurred in 21.9% of patients in the pantoprazole group and in 22.6% in the placebo group (RR, 0.96; 95% CI, 0.83-1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, compared with 4.2% in the placebo group, Dr. Krag and her coauthors wrote.

The findings are similar to other recently published results, which showed “no significant differences ... in the rates of death or infectious complications between patients receiving placebo or no prophylaxis and those receiving proton pump inhibitors,” the authors wrote.

Dr. Krag reported financial support from Innovation Fund Denmark, Ehrenreich’s Foundation, and several other organizations.

SOURCE: Krag M et al. N Engl J Med. 2018 Dec 6. doi: 10.1056/NEJMoa1714919.

This article was updated 12/6/18.

There was no significant difference in mortality between critically ill patients who received pantoprazole prophylaxis for gastrointestinal bleeding, and those who received placebo, new findings suggest.

In a multicenter, randomized trial of 3,298 adult patients at risk for gastrointestinal bleeding, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died at 90 days (relative risk, 1.02; 95% confidence interval, 0.91-1.13; P = .76). The results were published in the New England Journal of Medicine.

Patients were aged 18 years or older; had been admitted to the ICU for an acute condition in one of six international centers; and had at least one risk factor for gastrointestinal bleeding including shock, use of anticoagulant agents, renal replacement therapy, mechanical ventilation (expected to last more than 24 hours), any history of liver disease, or any history of or ongoing coagulopathy. A total of 1,645 patients were randomly assigned to receive 40 mg of intravenous pantoprazole once daily and 1,653 received placebo, reported Mette Krag, MD, of the department of intensive care at Rigshospitalet in Copenhagen, and her coauthors.

The primary outcome was 90-day mortality. Secondary outcomes were clinically important events in the ICU, clinically important gastrointestinal bleeding in the ICU, infectious adverse events in the ICU, and days alive without the use of life support within the 90-day period.

One or more clinically important events occurred in 21.9% of patients in the pantoprazole group and in 22.6% in the placebo group (RR, 0.96; 95% CI, 0.83-1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, compared with 4.2% in the placebo group, Dr. Krag and her coauthors wrote.

The findings are similar to other recently published results, which showed “no significant differences ... in the rates of death or infectious complications between patients receiving placebo or no prophylaxis and those receiving proton pump inhibitors,” the authors wrote.

Dr. Krag reported financial support from Innovation Fund Denmark, Ehrenreich’s Foundation, and several other organizations.

SOURCE: Krag M et al. N Engl J Med. 2018 Dec 6. doi: 10.1056/NEJMoa1714919.

This article was updated 12/6/18.

The FP recognized the severely sun damaged scalp as a major risk factor for skin cancers. He looked closely at the lesions and realized that the ulcerated areas were at particularly high risk for squamous cell carcinoma (SCC).

He performed broad shave biopsies with sufficient depth to obtain the needed diagnosis. (See the Watch & Learn video on “Shave biopsy.”) The pathology demonstrated that 2 of the 3 biopsy sites were positive for SCC (E and G were SCC, while F was read as actinic keratosis). Cutaneous SCC is a malignant tumor of keratinocytes. Most cutaneous SCCs arise from precursor lesions, often actinic keratoses. SCC usually spreads by local extension, but it is also capable of regional lymph node metastasis and distant metastasis.

Unsure of the margins of the tumors and aware that surgery of the scalp can be challenging, the FP referred the patient for Mohs surgery. The FP also provided counseling about sun avoidance, the consistent use of a hat outdoors, and the use of sunscreens when exposed to the sun.

The Mohs surgeon recommended field treatment with 5% fluorouracil cream twice daily for 4 weeks before surgery to minimize the amount of cutting that would be needed to clear the SCC from this diffusely sun-damaged scalp. After the 5% fluorouracil cream treatment, the surgeon waited 1 month to allow the scalp to heal before performing surgery.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Squamous cell carcinoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:999-1007.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.

The new third edition will be available in January 2019: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/.

You can also get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.

The FP recognized the severely sun damaged scalp as a major risk factor for skin cancers. He looked closely at the lesions and realized that the ulcerated areas were at particularly high risk for squamous cell carcinoma (SCC).

He performed broad shave biopsies with sufficient depth to obtain the needed diagnosis. (See the Watch & Learn video on “Shave biopsy.”) The pathology demonstrated that 2 of the 3 biopsy sites were positive for SCC (E and G were SCC, while F was read as actinic keratosis). Cutaneous SCC is a malignant tumor of keratinocytes. Most cutaneous SCCs arise from precursor lesions, often actinic keratoses. SCC usually spreads by local extension, but it is also capable of regional lymph node metastasis and distant metastasis.

Unsure of the margins of the tumors and aware that surgery of the scalp can be challenging, the FP referred the patient for Mohs surgery. The FP also provided counseling about sun avoidance, the consistent use of a hat outdoors, and the use of sunscreens when exposed to the sun.

The Mohs surgeon recommended field treatment with 5% fluorouracil cream twice daily for 4 weeks before surgery to minimize the amount of cutting that would be needed to clear the SCC from this diffusely sun-damaged scalp. After the 5% fluorouracil cream treatment, the surgeon waited 1 month to allow the scalp to heal before performing surgery.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Squamous cell carcinoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:999-1007.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.

The new third edition will be available in January 2019: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/.

You can also get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.

The FP recognized the severely sun damaged scalp as a major risk factor for skin cancers. He looked closely at the lesions and realized that the ulcerated areas were at particularly high risk for squamous cell carcinoma (SCC).

He performed broad shave biopsies with sufficient depth to obtain the needed diagnosis. (See the Watch & Learn video on “Shave biopsy.”) The pathology demonstrated that 2 of the 3 biopsy sites were positive for SCC (E and G were SCC, while F was read as actinic keratosis). Cutaneous SCC is a malignant tumor of keratinocytes. Most cutaneous SCCs arise from precursor lesions, often actinic keratoses. SCC usually spreads by local extension, but it is also capable of regional lymph node metastasis and distant metastasis.

Unsure of the margins of the tumors and aware that surgery of the scalp can be challenging, the FP referred the patient for Mohs surgery. The FP also provided counseling about sun avoidance, the consistent use of a hat outdoors, and the use of sunscreens when exposed to the sun.

The Mohs surgeon recommended field treatment with 5% fluorouracil cream twice daily for 4 weeks before surgery to minimize the amount of cutting that would be needed to clear the SCC from this diffusely sun-damaged scalp. After the 5% fluorouracil cream treatment, the surgeon waited 1 month to allow the scalp to heal before performing surgery.

‌

Photos and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Squamous cell carcinoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas of Family Medicine. 2nd ed. New York, NY: McGraw-Hill; 2013:999-1007.

To learn more about the Color Atlas of Family Medicine, see: www.amazon.com/Color-Family-Medicine-Richard-Usatine/dp/0071769641/.

The new third edition will be available in January 2019: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/.

You can also get the second edition of the Color Atlas of Family Medicine as an app by clicking on this link: usatinemedia.com.

Biosimilars for three widely used oncology drugs showed efficacy and safety in lung cancer and breast cancer similar to those of the reference products, according to findings reported at the 2018 annual meeting of the American Society of Clinical Oncology in Chicago.

Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, investigators reported at the annual ASCO meeting. The findings advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.

“Biosimilars are here,” said Michael A Thompson, MD, PhD, of Aurora Health Care in Milwaukee, Wisconsin, “[although] issues remain, including clinical decision support and pathway adoption, naming differences across the world, competition and lower prices versus the illusion of a free market, and adoption to decrease costs and increase value to our patients.” Dr Thompson was commenting during an invited discussion at the meeting. He is the medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health (also see Commentary at end of article).

Bevacizumab biosimilar

The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous non–small-cell lung cancer (NSCLC). Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.

The overall response rate by week 19, confirmed by week 25 – the trial’s primary endpoint – was 45.3% with the biosimilar and 44.6% with bevacizumab, reported lead author Mark A Socinski, MD, executive medical director of the Florida Hospital Cancer Institute in Orlando. The confidence interval (CI) for the risk difference fell within the equivalence margins set by European Union regulators (-13% and +13% for the 95% CI). And the confidence interval for the risk ratio fell within the equivalence margins set by the US Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).

Median progression-free survival (PFS) was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio [HR], 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, respectively, Dr Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.

Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the 2 agents. Patients also had similar rates of grade 3 or higher serious adverse events (AEs) and of fatal (grade 5) serious AEs with the biosimilar and bevacizumab (5.3% and 5.9%, respectively).

“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr Socinski summarized. “These results confirm the similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU.”

Funding Pfizer sponsored the REFLECTIONS trial. Disclosures Dr Socinski disclosed that his institution receives research funding from Pfizer. Source Socinski MA et al. A comparative clinical study of PF-06439535, a candidate bevacizumab biosimilar, and reference bevacizumab, in patients with advanced non-squamous non-small cell lung cancer. ASCO 2018, Abstract 109. https://meetinglibrary.asco.org/record/161702/abstract. Clinical trial registry number NCT02364999 https://clinicaltrials.gov/ct2/show/NCT02364999

Trastuzumab biosimilar

The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer. The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various AEs were essentially the same.

The 48-week results showed a median PFS of 11.1 months with trastuzumab-dkst and 11.1 months with trastuzumab (HR, 0.95; P = .842), reported senior investigator Hope S Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. “The overall survival is immature but is impressive at over 80% at 52 weeks,” she noted.

Presence of overall response at 24 weeks correlated with duration of PFS at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr Rugo commented.

Common AEs through week 48 were much the same as those seen at week 24, with few additional [events] occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell to a very low number and was identical between the 2 arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”

The 48-week rates of AEs of special interest – respiratory events, cardiac disorders, and infusion-related AEs – and of serious AEs were similar for the 2 agents.

“We didn’t see any additional serious cardiac events during monotherapy,” Dr Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.

“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.”

Dr Rugo emphasized that trastuzumab-dkst provides “an additional high-quality treatment option for patients with HER2+ breast cancers in any setting. This study shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”

Funding Mylan sponsored the HERITAGE trial. Disclosures Dr Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan. Source Manikhas A et al. Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: Toxicity, efficacy, and immunogenicity from the phase 3 Heritage trial. ASCO 2018, Abstract 110. https://meetinglibrary.asco.org/record/161572/abstract. Clinical trial registry number NCT02472964 https://clinicaltrials.gov/ct2/show/NCT02472964
 

Filgrastim biosimilar

Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of OB&GYN at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony-stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.

Data for the former came from PIONEER, a phase 3, randomized, controlled trial among patients with nonmetastatic breast cancer undergoing docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy in the neoadjuvant or adjuvant setting (Ann Oncol. 2015;26[9]:1948-53). Data for the latter came from MONITOR-GCSF, a postmarketing, open-label, observational cohort study among patients from 12 European countries receiving chemotherapy for various solid and hematologic malignancies (Support Care Cancer. 2016;24[2]:911-25).

Dr Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.

Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial/biosimilar population. Findings were similar for temperature exceeding 38.5°C in any cycle: 3.4% and 5.6%, respectively. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% and 74.3%) and higher rates of infection (15.5% and 7.9%) and hospitalization caused by febrile neutropenia (3.9% and 1.8%). Findings were essentially the same in cycle-level analyses.

The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 and 261 events, respectively) and skin/subcutaneous tissue disorders (5 and 258 events). “Seeing these data, you have to keep in mind that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”

Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.

“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr Harbeck commented. “Having seen the discrepancies in the data, I think it’s important to have randomized controlled trials to assess and monitor AEs for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
 

Funding Sandoz sponsored the PIONEER and MONITOR-GCSF trials. Disclosures Dr Harbeck disclosed that she has a consulting or advisory role with Sandoz. Source Harbeck N et al. Comparison of efficacy and safety of biosimilar filgrastim in a RCT (PIONEER) and real-world practice (MONITOR-GCSF). ASCO 2018, Abstract 111. https://meetinglibrary.asco.org/record/161688/abstract. Clinical trial registry number NCT01519700 https://clinicaltrials.gov/ct2/show/NCT01519700

Biosimilars for three widely used oncology drugs showed efficacy and safety in lung cancer and breast cancer similar to those of the reference products, according to findings reported at the 2018 annual meeting of the American Society of Clinical Oncology in Chicago.

Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, investigators reported at the annual ASCO meeting. The findings advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.

“Biosimilars are here,” said Michael A Thompson, MD, PhD, of Aurora Health Care in Milwaukee, Wisconsin, “[although] issues remain, including clinical decision support and pathway adoption, naming differences across the world, competition and lower prices versus the illusion of a free market, and adoption to decrease costs and increase value to our patients.” Dr Thompson was commenting during an invited discussion at the meeting. He is the medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health (also see Commentary at end of article).

Bevacizumab biosimilar

The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous non–small-cell lung cancer (NSCLC). Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.

The overall response rate by week 19, confirmed by week 25 – the trial’s primary endpoint – was 45.3% with the biosimilar and 44.6% with bevacizumab, reported lead author Mark A Socinski, MD, executive medical director of the Florida Hospital Cancer Institute in Orlando. The confidence interval (CI) for the risk difference fell within the equivalence margins set by European Union regulators (-13% and +13% for the 95% CI). And the confidence interval for the risk ratio fell within the equivalence margins set by the US Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).

Median progression-free survival (PFS) was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio [HR], 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, respectively, Dr Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.

Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the 2 agents. Patients also had similar rates of grade 3 or higher serious adverse events (AEs) and of fatal (grade 5) serious AEs with the biosimilar and bevacizumab (5.3% and 5.9%, respectively).

“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr Socinski summarized. “These results confirm the similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU.”

Funding Pfizer sponsored the REFLECTIONS trial. Disclosures Dr Socinski disclosed that his institution receives research funding from Pfizer. Source Socinski MA et al. A comparative clinical study of PF-06439535, a candidate bevacizumab biosimilar, and reference bevacizumab, in patients with advanced non-squamous non-small cell lung cancer. ASCO 2018, Abstract 109. https://meetinglibrary.asco.org/record/161702/abstract. Clinical trial registry number NCT02364999 https://clinicaltrials.gov/ct2/show/NCT02364999

Trastuzumab biosimilar

The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer. The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various AEs were essentially the same.

The 48-week results showed a median PFS of 11.1 months with trastuzumab-dkst and 11.1 months with trastuzumab (HR, 0.95; P = .842), reported senior investigator Hope S Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. “The overall survival is immature but is impressive at over 80% at 52 weeks,” she noted.

Presence of overall response at 24 weeks correlated with duration of PFS at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr Rugo commented.

Common AEs through week 48 were much the same as those seen at week 24, with few additional [events] occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell to a very low number and was identical between the 2 arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”

The 48-week rates of AEs of special interest – respiratory events, cardiac disorders, and infusion-related AEs – and of serious AEs were similar for the 2 agents.

“We didn’t see any additional serious cardiac events during monotherapy,” Dr Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.

“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.”

Dr Rugo emphasized that trastuzumab-dkst provides “an additional high-quality treatment option for patients with HER2+ breast cancers in any setting. This study shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”

Funding Mylan sponsored the HERITAGE trial. Disclosures Dr Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan. Source Manikhas A et al. Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: Toxicity, efficacy, and immunogenicity from the phase 3 Heritage trial. ASCO 2018, Abstract 110. https://meetinglibrary.asco.org/record/161572/abstract. Clinical trial registry number NCT02472964 https://clinicaltrials.gov/ct2/show/NCT02472964
 

Filgrastim biosimilar

Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of OB&GYN at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony-stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.

Data for the former came from PIONEER, a phase 3, randomized, controlled trial among patients with nonmetastatic breast cancer undergoing docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy in the neoadjuvant or adjuvant setting (Ann Oncol. 2015;26[9]:1948-53). Data for the latter came from MONITOR-GCSF, a postmarketing, open-label, observational cohort study among patients from 12 European countries receiving chemotherapy for various solid and hematologic malignancies (Support Care Cancer. 2016;24[2]:911-25).

Dr Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.

Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial/biosimilar population. Findings were similar for temperature exceeding 38.5°C in any cycle: 3.4% and 5.6%, respectively. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% and 74.3%) and higher rates of infection (15.5% and 7.9%) and hospitalization caused by febrile neutropenia (3.9% and 1.8%). Findings were essentially the same in cycle-level analyses.

The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 and 261 events, respectively) and skin/subcutaneous tissue disorders (5 and 258 events). “Seeing these data, you have to keep in mind that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”

Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.

“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr Harbeck commented. “Having seen the discrepancies in the data, I think it’s important to have randomized controlled trials to assess and monitor AEs for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
 

Funding Sandoz sponsored the PIONEER and MONITOR-GCSF trials. Disclosures Dr Harbeck disclosed that she has a consulting or advisory role with Sandoz. Source Harbeck N et al. Comparison of efficacy and safety of biosimilar filgrastim in a RCT (PIONEER) and real-world practice (MONITOR-GCSF). ASCO 2018, Abstract 111. https://meetinglibrary.asco.org/record/161688/abstract. Clinical trial registry number NCT01519700 https://clinicaltrials.gov/ct2/show/NCT01519700

Biosimilars for three widely used oncology drugs showed efficacy and safety in lung cancer and breast cancer similar to those of the reference products, according to findings reported at the 2018 annual meeting of the American Society of Clinical Oncology in Chicago.

Oncology biosimilars for bevacizumab (Avastin), trastuzumab (Herceptin), and filgrastim (Neupogen and others) have yielded positive results in various patient populations and clinical settings, investigators reported at the annual ASCO meeting. The findings advance the promise of new agents that have no clinically meaningful differences in efficacy and safety when compared with their reference drugs but have substantially lower cost.

“Biosimilars are here,” said Michael A Thompson, MD, PhD, of Aurora Health Care in Milwaukee, Wisconsin, “[although] issues remain, including clinical decision support and pathway adoption, naming differences across the world, competition and lower prices versus the illusion of a free market, and adoption to decrease costs and increase value to our patients.” Dr Thompson was commenting during an invited discussion at the meeting. He is the medical director of the Early Phase Cancer Research Program and the Oncology Precision Medicine Program at Aurora Health (also see Commentary at end of article).

Bevacizumab biosimilar

The REFLECTIONS trial (NCT02364999) was a multinational, first-line, randomized, controlled trial among 719 patients with advanced nonsquamous non–small-cell lung cancer (NSCLC). Patients were randomized to paclitaxel and carboplatin chemotherapy plus either bevacizumab (sourced from the European Union) or the candidate bevacizumab biosimilar PF-06439535 on a double-blind basis, followed by monotherapy with the same assigned agent.

The overall response rate by week 19, confirmed by week 25 – the trial’s primary endpoint – was 45.3% with the biosimilar and 44.6% with bevacizumab, reported lead author Mark A Socinski, MD, executive medical director of the Florida Hospital Cancer Institute in Orlando. The confidence interval (CI) for the risk difference fell within the equivalence margins set by European Union regulators (-13% and +13% for the 95% CI). And the confidence interval for the risk ratio fell within the equivalence margins set by the US Food and Drug Administration (0.73 and 1.37 for the 90% CI) and Japanese regulators (0.729 and 1.371 for the 95% CI).

Median progression-free survival (PFS) was 9.0 months with the biosimilar and 7.7 months with bevacizumab (hazard ratio [HR], 0.974; P = .814), and corresponding 1-year rates were 30.8% and 29.3%, respectively, Dr Socinski reported. Median overall survival was 18.4 months and 17.8 months (HR, 1.001; P = .991), and corresponding 1-year rates were 66.4% and 68.8%.

Rates of grade 3 or higher hypertension, cardiac disorders, and bleeding did not differ significantly with the 2 agents. Patients also had similar rates of grade 3 or higher serious adverse events (AEs) and of fatal (grade 5) serious AEs with the biosimilar and bevacizumab (5.3% and 5.9%, respectively).

“Similarity between PF-06439535 and bevacizumab-EU was demonstrated for the primary efficacy endpoint of overall response rate. ... There were no clinically meaningful differences in safety profile shown in this trial, and similar pharmacokinetic and immunogenicity results were seen across treatment groups,” Dr Socinski summarized. “These results confirm the similarity demonstrated in earlier analytical, nonclinical, and clinical studies of PF-06439535 with bevacizumab-EU.”

Funding Pfizer sponsored the REFLECTIONS trial. Disclosures Dr Socinski disclosed that his institution receives research funding from Pfizer. Source Socinski MA et al. A comparative clinical study of PF-06439535, a candidate bevacizumab biosimilar, and reference bevacizumab, in patients with advanced non-squamous non-small cell lung cancer. ASCO 2018, Abstract 109. https://meetinglibrary.asco.org/record/161702/abstract. Clinical trial registry number NCT02364999 https://clinicaltrials.gov/ct2/show/NCT02364999

Trastuzumab biosimilar

The phase 3 HERITAGE trial was a first-line, randomized, controlled trial that compared biosimilar trastuzumab-dkst (Ogivri) with trastuzumab in combination with taxane chemotherapy and then as maintenance monotherapy in 458 patients with HER2+ advanced breast cancer. The 24-week results, previously reported (JAMA. 2017 Jan 3;317[1]:37-47), showed a similar overall response rate with each agent when combined with chemotherapy. Rates of various AEs were essentially the same.

The 48-week results showed a median PFS of 11.1 months with trastuzumab-dkst and 11.1 months with trastuzumab (HR, 0.95; P = .842), reported senior investigator Hope S Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center. “The overall survival is immature but is impressive at over 80% at 52 weeks,” she noted.

Presence of overall response at 24 weeks correlated with duration of PFS at 48 weeks (biserial r = .752). “Additional patients achieved a response during the monotherapy portion of the treatment, which is intriguing and clearly emphasizes the importance of monotherapy, as well as the importance of having alternate agents at lower cost available,” Dr Rugo commented.

Common AEs through week 48 were much the same as those seen at week 24, with few additional [events] occurring during monotherapy. “No new safety issues were observed, and in fact, toxicity during monotherapy was quite minor,” she noted. “One thing that’s interesting here is that there was more arthralgia during the first 24 weeks with trastuzumab-dkst than with trastuzumab, but in monotherapy, this fell to a very low number and was identical between the 2 arms. Paclitaxel, which people stayed on for longer [with the biosimilar], may have been the cause of this.”

The 48-week rates of AEs of special interest – respiratory events, cardiac disorders, and infusion-related AEs – and of serious AEs were similar for the 2 agents.

“We didn’t see any additional serious cardiac events during monotherapy,” Dr Rugo noted. Mean and median left ventricular ejection fraction over 48 weeks were similar, as was the rate of LVEF, which dropped below 50% (4.0% with trastuzumab-dkst and 3.3% with trastuzumab). The incidences of antidrug antibody and neutralizing antibody were also comparably low in both groups.

“HERITAGE data, now at week 48, supports trastuzumab-dkst as a biosimilar to trastuzumab in all approved indications,” Dr Rugo said. “Final overall survival will be assessed after 36 months or after 240 deaths, whichever occurs first. Based on current data, this is predicted to conclude by the end of 2018, with final overall survival data available next year.”

Dr Rugo emphasized that trastuzumab-dkst provides “an additional high-quality treatment option for patients with HER2+ breast cancers in any setting. This study shows that biosimilars offer the potential for worldwide cost savings and improved access to life-saving therapies. It’s sobering to think that the patients enrolled in this study would not otherwise have had access to continued trastuzumab therapy, and so many of them are still alive with longer follow-up.”

Funding Mylan sponsored the HERITAGE trial. Disclosures Dr Rugo disclosed that she receives travel, accommodations, and/or expenses from Mylan. Source Manikhas A et al. Biosimilar trastuzumab-dkst monotherapy versus trastuzumab monotherapy after combination therapy: Toxicity, efficacy, and immunogenicity from the phase 3 Heritage trial. ASCO 2018, Abstract 110. https://meetinglibrary.asco.org/record/161572/abstract. Clinical trial registry number NCT02472964 https://clinicaltrials.gov/ct2/show/NCT02472964
 

Filgrastim biosimilar

Investigators led by Nadia Harbeck, MD, PhD, head of the Breast Center and chair for Conservative Oncology in the department of OB&GYN at the University of Munich (Germany), compared efficacy of filgrastim-sndz (Zarxio), a biosimilar of filgrastim (recombinant granulocyte colony-stimulating factor, or G-CSF), in a trial population with that of a real-world population of women receiving chemotherapy for breast cancer.

Data for the former came from PIONEER, a phase 3, randomized, controlled trial among patients with nonmetastatic breast cancer undergoing docetaxel, doxorubicin, and cyclophosphamide (TAC) chemotherapy in the neoadjuvant or adjuvant setting (Ann Oncol. 2015;26[9]:1948-53). Data for the latter came from MONITOR-GCSF, a postmarketing, open-label, observational cohort study among patients from 12 European countries receiving chemotherapy for various solid and hematologic malignancies (Support Care Cancer. 2016;24[2]:911-25).

Dr Harbeck and her colleagues compared 217 women who had nonmetastatic breast cancer from the trial with 466 women who had any-stage breast cancer (42% metastatic) from the real-world cohort.

Results showed that the 6.2% rate of chemotherapy-induced febrile neutropenia in any cycle seen in the real-world population was much the same as the 5.1% rate seen previously in the trial/biosimilar population. Findings were similar for temperature exceeding 38.5°C in any cycle: 3.4% and 5.6%, respectively. The real-world population had a lower rate of severe neutropenia than did the trial population (19.5% and 74.3%) and higher rates of infection (15.5% and 7.9%) and hospitalization caused by febrile neutropenia (3.9% and 1.8%). Findings were essentially the same in cycle-level analyses.

The real-world cohort had many fewer any-severity safety events of special interest than did the trial cohort, such as musculoskeletal/connective tissue disorders (20 and 261 events, respectively) and skin/subcutaneous tissue disorders (5 and 258 events). “Seeing these data, you have to keep in mind that the patients received totally different chemotherapy. TAC chemotherapy has a lot of chemotherapy-associated side effects,” Dr Harbeck noted. “The other thing is that MONITOR was a real-world database, and one could assume that there is some underreporting of events that are not directly correlated to the events that are of particular interest.”

Additional results available only from the trial showed that no patients developed binding or neutralizing antibodies against G-CSF.

“From a clinician’s point of view, it is very reassuring that we did not see any other safety signals in the real-world data than we saw in the randomized controlled trial and the efficacy was very, very similar,” Dr Harbeck commented. “Having seen the discrepancies in the data, I think it’s important to have randomized controlled trials to assess and monitor AEs for registration purposes and real-world evidence to reflect the daily clinical routine,” she concluded.
 

Funding Sandoz sponsored the PIONEER and MONITOR-GCSF trials. Disclosures Dr Harbeck disclosed that she has a consulting or advisory role with Sandoz. Source Harbeck N et al. Comparison of efficacy and safety of biosimilar filgrastim in a RCT (PIONEER) and real-world practice (MONITOR-GCSF). ASCO 2018, Abstract 111. https://meetinglibrary.asco.org/record/161688/abstract. Clinical trial registry number NCT01519700 https://clinicaltrials.gov/ct2/show/NCT01519700

Individuals who have both an elevated lipoprotein levels and a family history of coronary heart disease are at a considerably higher long-term risk for ASCVD. Also today, a device malfunction muddles results for insulin inhaler for Alzheimer’s, it’s time for universal hepatitis C virus screening in the ED, and there is a date for the 2019 Sickle Cell Disease guidelines.

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Individuals who have both an elevated lipoprotein levels and a family history of coronary heart disease are at a considerably higher long-term risk for ASCVD. Also today, a device malfunction muddles results for insulin inhaler for Alzheimer’s, it’s time for universal hepatitis C virus screening in the ED, and there is a date for the 2019 Sickle Cell Disease guidelines.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

Individuals who have both an elevated lipoprotein levels and a family history of coronary heart disease are at a considerably higher long-term risk for ASCVD. Also today, a device malfunction muddles results for insulin inhaler for Alzheimer’s, it’s time for universal hepatitis C virus screening in the ED, and there is a date for the 2019 Sickle Cell Disease guidelines.

Amazon Alexa

Apple Podcasts

Google Podcasts

Spotify
 

The development of biologic therapies has led to some of the most significant advances in the treatment of cancer, but these drugs are also very expensive. As patents for the biologics begin to expire, the development of biosimilars has the potential to dramatically cut therapy costs thereby making the therapies more readily accessible to patients. Here, we discuss biosimilar development and the challenges that need to be overcome to create a robust market.

Biosimilar, not generic

Biologic therapies are derived from living organisms and include the targeted monoclonal antibodies (mAbs) and cell-based therapies that have revolutionized the treatment of certain cancer types. Yet, their greater complexity makes them more difficult to manufacture, store, and administer, making them a costly therapeutic option that ultimately drives up health care costs. According to a 2011 drug expenditure analysis, biologic therapies accounted for more than half of the total expenditure on anticancer drugs in the US health care system.^1,2

Generally, when drug patents expire, other companies can develop their own identical generic versions to increase competition in the marketplace and drive down costs. However, the paradigm for generic development cannot be applied to biologic therapies because the way in which they are manufactured makes it impossible to generate an identical copy.

Instead, the Biologics Price Competition and Innovation Act, a provision of the Patient Protection and Affordable Care Act, has allowed for submission of an application for “licensure of a biologic product based on its similarity to a licensed biologic product”.³

These “biosimilars” have been positioned as game-changers in oncology, with the potential to reduce costs and improve access to biologic therapies. With the patents on several blockbuster cancer biologics already expired or due to expire by 2020, an increasing number of biosimilars are being developed.⁴

Totality of evidence

Biosimilars require more rigorous testing than generics, but they don’t require the same type of scientific data that the original biologic products, termed “reference products,” did. Therefore, they are governed by legislation unique to them and approved by different regulatory pathways. The US Food and Drug Administration (FDA) has established a unique shortened regulatory pathway for their approval, known as the 351(k) pathway. So whereas the pathway for reference products is geared toward demonstrating patient benefit, biosimilars are required instead to show equivalence to the reference product.⁵

Biosimilars are produced through reverse engineering the reference product. Then, through a stepwise process, to generate what the FDA calls a “totality of evidence,” biosimilar manufacturers must demonstrate structural and functional similarities (through comparative quality studies) and comparable pharmacokinetics and pharmacodynamics (through comparative nonclinical and clinical studies) to the reference product. Final approval is based on 1 or more comparative clinical studies performed in the most sensitive patient population(s) (Figure 1).⁶

A flurry of approvals

The first biosimilar approvals in oncology in the United States came in the supportive care niche (Table 1). Filgrastim-sndz (Zarxio), approved in March 2015, is a biosimilar of the granulocyte-macrophage colony stimulating factor (G-CSF) analog filgrastim (Neupogen). Owing to its mechanism of action in stimulating the production of neutrophils in the bone marrow, filgrastim is used to help reduce the risk or severity of neutropenia in patients undergoing myelosuppressive chemotherapy regimens.

Filgrastim-sndz was approved for use across all 5 indications for which the reference product is approved, based on the totality of evidence, which included results from the key phase 3 PIONEER study.⁹ Market entry was initially delayed by lawsuits filed by Amgen, the maker of the reference product, but the biosimilar was subsequently cleared by the US Court of Appeals for the Federal Circuit. The wholesale acquisition cost (WAC) for a 300µg syringe is $324.30 for filgrastim and $275.66 figrastim-sndz, representing a 15% reduction on the reference product.¹⁰

9,19-22

Biosimilars in development

While numerous other biosimilars of filgrastim and pegfilgrastim are in development, the major focus has been on the development of more biosimilars to treat cancer (Table 3). BLAs have been submitted for 4 biosimilars of trastuzumab and 1 bevacizumab biosimilar. Approval for several of the trastuzumab biosimilars has been delayed by CRLs from the FDA, mostly regarding issues with the manufacturing process or facility. Several other trastuzumab and bevacizumab biosimilars are in late-stage clinical trials.

The results of several phase 3 comparative clinical trials were recently published or reported at annual conferences. Pfizer’s PF-05280014 was compared with the European Union (EU)–approved trastuzumab, both in combination with paclitaxel, in patients with previously untreated HER2-positive metastatic breast cancer. Data reported at the European Society for Medical Oncology congress in 2017 demonstrated equivalence between the reference product and biosimilar in overall response rate (ORR).²³

Another recently published trial compared this biosimilar to EU-trastuzumab, both in combination with carboplatin and docetaxel, as neoadjuvant treatment for patients with resectable HER2-positive breast cancer. Among 226 patients randomized to receive 8 mg/kg in cycle 1 and 6 mg/kg thereafter of the biosimilar or reference product, every 3 weeks for 6 cycles, the pathologic complete response (pCR) rates were 47% and 50%, respectively.²⁴

The results of a phase 3 study comparing Samsung Bioepis/Merck’s joint offering SB3 were recently published. A total of 875 patients were randomized 1:1 to receive SB3 or reference trastuzumab in combination with chemotherapy (4 cycles docetaxel followed by 4 cycles 5-fluorouracil/epirubicin/cyclophosphamide) prior to surgery, followed by 10 cycles of adjuvant SB3 or trastuzumab reference. Rates of event-free survival (EFS) were comparable between the 2 groups at 12 months (93.7% vs 96.1%, respectively).²⁵

Amgen’s ABP980 was evaluated in the phase 3 LILAC trial, which measured the effect of the biosimilar on pCR in women with HER2-positive early breast cancer compared with reference trastuzumab. After 4 cycles of run-in anthracycline-based chemotherapy, ABP980 or reference trastuzumab were administered in combination with paclitaxel. This was followed by surgery and then ABP980 or reference trastuzumab in the adjuvant setting for up to 1 year, with the option to continue on the same drug as the neoadjuvant setting or to switch to the other. Among 696 assessable patients, the pCR rates were 48% and 42%, respectively.²⁶

Most advanced in clinical testing among the upcoming bevacizumab biosimilars is Pfizer’s PF-06439535, for which the results of a phase 3 comparative trial were presented at the 2018 annual meeting of the American Society for Clinical Oncology. PF-06439535 was compared with the EU-approved bevacizumab, both in combination with paclitaxel and carboplatin, as first-line therapy for patients with advanced non-squamous NSCLC. Among 719 patients, the primary endpoint of ORR was 45.3% and 44.6%, respectively.²⁷

Biosimilars of a third blockbuster cancer drug, the CD20-targeting mAb rituximab (Rituxan) are also in development and FDA approval is pending for 2. The patent for Rituxan expired in 2016, so these drugs could hit the market as soon as they are approved.

In a race to the finish for the first US-approved rituximab biosimilar, Celltrion-Teva’s CT-P10 (Truxima) seems most likely to come first; the Oncologic Drugs Advisory Committee voted unanimously in October 2018 to recommend its approval. Phase 3 comparative data were recently published; patients with newly diagnosed advanced-stage follicular lymphoma were randomized to receive intravenous infusions of 375 mg/m² CT-P10 or reference rituximab, both in combination with cyclophosphamide, vincristine, and prednisone, on day 1 of 8 21-day cycles. The ORRs were identical (92.6%) for both drugs, pharmacokinetics data also suggested bioequivalence, and the incidence of AEs was also comparable (83% vs 80%).²⁸

Biosimilars of the epidermal growth factor receptor (EGFR)-targeting mAb cetuximab are also listed in the pipeline for several biosimilar developers, but there is no indication of their developmental status as yet and no clinical trials are ongoing in the US.

Sorrento is developing STI-001, a cetuximab biosimilar, and reported that a phase 3 trial had been completed. Instead of a comparison with the reference product, however, the trial compared STI-001 in combination with irinotecan with irinotecan alone. They reported significantly higher ORR, PFS, and OS with the biosimilar compared with irinotecan alone, and a significant increase over historical data with the reference product, as well as fewer side effects and immunogenicity, which they attribute to its manufacture in a different cell line. However, no data has been published and no trials are ongoing in the United States, so the status of its development remains unclear.²⁹
 

Challenges to a robust market

It is an exciting time for biosimilars, with many approvals and drugs being brought to market in the US in the past several years and more poised to follow suit as patents expire. Yet many challenges remain around the growth of a robust biosimilars market.

Several surveys conducted in recent years have demonstrated suboptimal knowledge of all aspects of biosimilars and highlighted the need for evidence-based education across specialties.^30,31 In response, the FDA recently announced that it was launching an educational campaign to further understanding of biosimilars, including naming conventions (Figure 2).^32,33 Numerous other medical professional societies have produced or are in the process of producing biosimilar guidelines.

The development of biologic therapies has led to some of the most significant advances in the treatment of cancer, but these drugs are also very expensive. As patents for the biologics begin to expire, the development of biosimilars has the potential to dramatically cut therapy costs thereby making the therapies more readily accessible to patients. Here, we discuss biosimilar development and the challenges that need to be overcome to create a robust market.

Biosimilar, not generic

Biologic therapies are derived from living organisms and include the targeted monoclonal antibodies (mAbs) and cell-based therapies that have revolutionized the treatment of certain cancer types. Yet, their greater complexity makes them more difficult to manufacture, store, and administer, making them a costly therapeutic option that ultimately drives up health care costs. According to a 2011 drug expenditure analysis, biologic therapies accounted for more than half of the total expenditure on anticancer drugs in the US health care system.^1,2

Generally, when drug patents expire, other companies can develop their own identical generic versions to increase competition in the marketplace and drive down costs. However, the paradigm for generic development cannot be applied to biologic therapies because the way in which they are manufactured makes it impossible to generate an identical copy.

Instead, the Biologics Price Competition and Innovation Act, a provision of the Patient Protection and Affordable Care Act, has allowed for submission of an application for “licensure of a biologic product based on its similarity to a licensed biologic product”.³

These “biosimilars” have been positioned as game-changers in oncology, with the potential to reduce costs and improve access to biologic therapies. With the patents on several blockbuster cancer biologics already expired or due to expire by 2020, an increasing number of biosimilars are being developed.⁴

Totality of evidence

Biosimilars require more rigorous testing than generics, but they don’t require the same type of scientific data that the original biologic products, termed “reference products,” did. Therefore, they are governed by legislation unique to them and approved by different regulatory pathways. The US Food and Drug Administration (FDA) has established a unique shortened regulatory pathway for their approval, known as the 351(k) pathway. So whereas the pathway for reference products is geared toward demonstrating patient benefit, biosimilars are required instead to show equivalence to the reference product.⁵

Biosimilars are produced through reverse engineering the reference product. Then, through a stepwise process, to generate what the FDA calls a “totality of evidence,” biosimilar manufacturers must demonstrate structural and functional similarities (through comparative quality studies) and comparable pharmacokinetics and pharmacodynamics (through comparative nonclinical and clinical studies) to the reference product. Final approval is based on 1 or more comparative clinical studies performed in the most sensitive patient population(s) (Figure 1).⁶

A flurry of approvals

The first biosimilar approvals in oncology in the United States came in the supportive care niche (Table 1). Filgrastim-sndz (Zarxio), approved in March 2015, is a biosimilar of the granulocyte-macrophage colony stimulating factor (G-CSF) analog filgrastim (Neupogen). Owing to its mechanism of action in stimulating the production of neutrophils in the bone marrow, filgrastim is used to help reduce the risk or severity of neutropenia in patients undergoing myelosuppressive chemotherapy regimens.

Filgrastim-sndz was approved for use across all 5 indications for which the reference product is approved, based on the totality of evidence, which included results from the key phase 3 PIONEER study.⁹ Market entry was initially delayed by lawsuits filed by Amgen, the maker of the reference product, but the biosimilar was subsequently cleared by the US Court of Appeals for the Federal Circuit. The wholesale acquisition cost (WAC) for a 300µg syringe is $324.30 for filgrastim and $275.66 figrastim-sndz, representing a 15% reduction on the reference product.¹⁰

9,19-22

Biosimilars in development

While numerous other biosimilars of filgrastim and pegfilgrastim are in development, the major focus has been on the development of more biosimilars to treat cancer (Table 3). BLAs have been submitted for 4 biosimilars of trastuzumab and 1 bevacizumab biosimilar. Approval for several of the trastuzumab biosimilars has been delayed by CRLs from the FDA, mostly regarding issues with the manufacturing process or facility. Several other trastuzumab and bevacizumab biosimilars are in late-stage clinical trials.

The results of several phase 3 comparative clinical trials were recently published or reported at annual conferences. Pfizer’s PF-05280014 was compared with the European Union (EU)–approved trastuzumab, both in combination with paclitaxel, in patients with previously untreated HER2-positive metastatic breast cancer. Data reported at the European Society for Medical Oncology congress in 2017 demonstrated equivalence between the reference product and biosimilar in overall response rate (ORR).²³

Another recently published trial compared this biosimilar to EU-trastuzumab, both in combination with carboplatin and docetaxel, as neoadjuvant treatment for patients with resectable HER2-positive breast cancer. Among 226 patients randomized to receive 8 mg/kg in cycle 1 and 6 mg/kg thereafter of the biosimilar or reference product, every 3 weeks for 6 cycles, the pathologic complete response (pCR) rates were 47% and 50%, respectively.²⁴

The results of a phase 3 study comparing Samsung Bioepis/Merck’s joint offering SB3 were recently published. A total of 875 patients were randomized 1:1 to receive SB3 or reference trastuzumab in combination with chemotherapy (4 cycles docetaxel followed by 4 cycles 5-fluorouracil/epirubicin/cyclophosphamide) prior to surgery, followed by 10 cycles of adjuvant SB3 or trastuzumab reference. Rates of event-free survival (EFS) were comparable between the 2 groups at 12 months (93.7% vs 96.1%, respectively).²⁵

Amgen’s ABP980 was evaluated in the phase 3 LILAC trial, which measured the effect of the biosimilar on pCR in women with HER2-positive early breast cancer compared with reference trastuzumab. After 4 cycles of run-in anthracycline-based chemotherapy, ABP980 or reference trastuzumab were administered in combination with paclitaxel. This was followed by surgery and then ABP980 or reference trastuzumab in the adjuvant setting for up to 1 year, with the option to continue on the same drug as the neoadjuvant setting or to switch to the other. Among 696 assessable patients, the pCR rates were 48% and 42%, respectively.²⁶

Most advanced in clinical testing among the upcoming bevacizumab biosimilars is Pfizer’s PF-06439535, for which the results of a phase 3 comparative trial were presented at the 2018 annual meeting of the American Society for Clinical Oncology. PF-06439535 was compared with the EU-approved bevacizumab, both in combination with paclitaxel and carboplatin, as first-line therapy for patients with advanced non-squamous NSCLC. Among 719 patients, the primary endpoint of ORR was 45.3% and 44.6%, respectively.²⁷

Biosimilars of a third blockbuster cancer drug, the CD20-targeting mAb rituximab (Rituxan) are also in development and FDA approval is pending for 2. The patent for Rituxan expired in 2016, so these drugs could hit the market as soon as they are approved.

In a race to the finish for the first US-approved rituximab biosimilar, Celltrion-Teva’s CT-P10 (Truxima) seems most likely to come first; the Oncologic Drugs Advisory Committee voted unanimously in October 2018 to recommend its approval. Phase 3 comparative data were recently published; patients with newly diagnosed advanced-stage follicular lymphoma were randomized to receive intravenous infusions of 375 mg/m² CT-P10 or reference rituximab, both in combination with cyclophosphamide, vincristine, and prednisone, on day 1 of 8 21-day cycles. The ORRs were identical (92.6%) for both drugs, pharmacokinetics data also suggested bioequivalence, and the incidence of AEs was also comparable (83% vs 80%).²⁸

Biosimilars of the epidermal growth factor receptor (EGFR)-targeting mAb cetuximab are also listed in the pipeline for several biosimilar developers, but there is no indication of their developmental status as yet and no clinical trials are ongoing in the US.

Sorrento is developing STI-001, a cetuximab biosimilar, and reported that a phase 3 trial had been completed. Instead of a comparison with the reference product, however, the trial compared STI-001 in combination with irinotecan with irinotecan alone. They reported significantly higher ORR, PFS, and OS with the biosimilar compared with irinotecan alone, and a significant increase over historical data with the reference product, as well as fewer side effects and immunogenicity, which they attribute to its manufacture in a different cell line. However, no data has been published and no trials are ongoing in the United States, so the status of its development remains unclear.²⁹
 

Challenges to a robust market

It is an exciting time for biosimilars, with many approvals and drugs being brought to market in the US in the past several years and more poised to follow suit as patents expire. Yet many challenges remain around the growth of a robust biosimilars market.

Several surveys conducted in recent years have demonstrated suboptimal knowledge of all aspects of biosimilars and highlighted the need for evidence-based education across specialties.^30,31 In response, the FDA recently announced that it was launching an educational campaign to further understanding of biosimilars, including naming conventions (Figure 2).^32,33 Numerous other medical professional societies have produced or are in the process of producing biosimilar guidelines.

The development of biologic therapies has led to some of the most significant advances in the treatment of cancer, but these drugs are also very expensive. As patents for the biologics begin to expire, the development of biosimilars has the potential to dramatically cut therapy costs thereby making the therapies more readily accessible to patients. Here, we discuss biosimilar development and the challenges that need to be overcome to create a robust market.

Biosimilar, not generic

Biologic therapies are derived from living organisms and include the targeted monoclonal antibodies (mAbs) and cell-based therapies that have revolutionized the treatment of certain cancer types. Yet, their greater complexity makes them more difficult to manufacture, store, and administer, making them a costly therapeutic option that ultimately drives up health care costs. According to a 2011 drug expenditure analysis, biologic therapies accounted for more than half of the total expenditure on anticancer drugs in the US health care system.^1,2

Generally, when drug patents expire, other companies can develop their own identical generic versions to increase competition in the marketplace and drive down costs. However, the paradigm for generic development cannot be applied to biologic therapies because the way in which they are manufactured makes it impossible to generate an identical copy.

Instead, the Biologics Price Competition and Innovation Act, a provision of the Patient Protection and Affordable Care Act, has allowed for submission of an application for “licensure of a biologic product based on its similarity to a licensed biologic product”.³

These “biosimilars” have been positioned as game-changers in oncology, with the potential to reduce costs and improve access to biologic therapies. With the patents on several blockbuster cancer biologics already expired or due to expire by 2020, an increasing number of biosimilars are being developed.⁴

Totality of evidence

Biosimilars require more rigorous testing than generics, but they don’t require the same type of scientific data that the original biologic products, termed “reference products,” did. Therefore, they are governed by legislation unique to them and approved by different regulatory pathways. The US Food and Drug Administration (FDA) has established a unique shortened regulatory pathway for their approval, known as the 351(k) pathway. So whereas the pathway for reference products is geared toward demonstrating patient benefit, biosimilars are required instead to show equivalence to the reference product.⁵

Biosimilars are produced through reverse engineering the reference product. Then, through a stepwise process, to generate what the FDA calls a “totality of evidence,” biosimilar manufacturers must demonstrate structural and functional similarities (through comparative quality studies) and comparable pharmacokinetics and pharmacodynamics (through comparative nonclinical and clinical studies) to the reference product. Final approval is based on 1 or more comparative clinical studies performed in the most sensitive patient population(s) (Figure 1).⁶

A flurry of approvals

The first biosimilar approvals in oncology in the United States came in the supportive care niche (Table 1). Filgrastim-sndz (Zarxio), approved in March 2015, is a biosimilar of the granulocyte-macrophage colony stimulating factor (G-CSF) analog filgrastim (Neupogen). Owing to its mechanism of action in stimulating the production of neutrophils in the bone marrow, filgrastim is used to help reduce the risk or severity of neutropenia in patients undergoing myelosuppressive chemotherapy regimens.

Filgrastim-sndz was approved for use across all 5 indications for which the reference product is approved, based on the totality of evidence, which included results from the key phase 3 PIONEER study.⁹ Market entry was initially delayed by lawsuits filed by Amgen, the maker of the reference product, but the biosimilar was subsequently cleared by the US Court of Appeals for the Federal Circuit. The wholesale acquisition cost (WAC) for a 300µg syringe is $324.30 for filgrastim and $275.66 figrastim-sndz, representing a 15% reduction on the reference product.¹⁰

9,19-22

Biosimilars in development

While numerous other biosimilars of filgrastim and pegfilgrastim are in development, the major focus has been on the development of more biosimilars to treat cancer (Table 3). BLAs have been submitted for 4 biosimilars of trastuzumab and 1 bevacizumab biosimilar. Approval for several of the trastuzumab biosimilars has been delayed by CRLs from the FDA, mostly regarding issues with the manufacturing process or facility. Several other trastuzumab and bevacizumab biosimilars are in late-stage clinical trials.

The results of several phase 3 comparative clinical trials were recently published or reported at annual conferences. Pfizer’s PF-05280014 was compared with the European Union (EU)–approved trastuzumab, both in combination with paclitaxel, in patients with previously untreated HER2-positive metastatic breast cancer. Data reported at the European Society for Medical Oncology congress in 2017 demonstrated equivalence between the reference product and biosimilar in overall response rate (ORR).²³

Another recently published trial compared this biosimilar to EU-trastuzumab, both in combination with carboplatin and docetaxel, as neoadjuvant treatment for patients with resectable HER2-positive breast cancer. Among 226 patients randomized to receive 8 mg/kg in cycle 1 and 6 mg/kg thereafter of the biosimilar or reference product, every 3 weeks for 6 cycles, the pathologic complete response (pCR) rates were 47% and 50%, respectively.²⁴

The results of a phase 3 study comparing Samsung Bioepis/Merck’s joint offering SB3 were recently published. A total of 875 patients were randomized 1:1 to receive SB3 or reference trastuzumab in combination with chemotherapy (4 cycles docetaxel followed by 4 cycles 5-fluorouracil/epirubicin/cyclophosphamide) prior to surgery, followed by 10 cycles of adjuvant SB3 or trastuzumab reference. Rates of event-free survival (EFS) were comparable between the 2 groups at 12 months (93.7% vs 96.1%, respectively).²⁵

Amgen’s ABP980 was evaluated in the phase 3 LILAC trial, which measured the effect of the biosimilar on pCR in women with HER2-positive early breast cancer compared with reference trastuzumab. After 4 cycles of run-in anthracycline-based chemotherapy, ABP980 or reference trastuzumab were administered in combination with paclitaxel. This was followed by surgery and then ABP980 or reference trastuzumab in the adjuvant setting for up to 1 year, with the option to continue on the same drug as the neoadjuvant setting or to switch to the other. Among 696 assessable patients, the pCR rates were 48% and 42%, respectively.²⁶

Most advanced in clinical testing among the upcoming bevacizumab biosimilars is Pfizer’s PF-06439535, for which the results of a phase 3 comparative trial were presented at the 2018 annual meeting of the American Society for Clinical Oncology. PF-06439535 was compared with the EU-approved bevacizumab, both in combination with paclitaxel and carboplatin, as first-line therapy for patients with advanced non-squamous NSCLC. Among 719 patients, the primary endpoint of ORR was 45.3% and 44.6%, respectively.²⁷

Biosimilars of a third blockbuster cancer drug, the CD20-targeting mAb rituximab (Rituxan) are also in development and FDA approval is pending for 2. The patent for Rituxan expired in 2016, so these drugs could hit the market as soon as they are approved.

In a race to the finish for the first US-approved rituximab biosimilar, Celltrion-Teva’s CT-P10 (Truxima) seems most likely to come first; the Oncologic Drugs Advisory Committee voted unanimously in October 2018 to recommend its approval. Phase 3 comparative data were recently published; patients with newly diagnosed advanced-stage follicular lymphoma were randomized to receive intravenous infusions of 375 mg/m² CT-P10 or reference rituximab, both in combination with cyclophosphamide, vincristine, and prednisone, on day 1 of 8 21-day cycles. The ORRs were identical (92.6%) for both drugs, pharmacokinetics data also suggested bioequivalence, and the incidence of AEs was also comparable (83% vs 80%).²⁸

Biosimilars of the epidermal growth factor receptor (EGFR)-targeting mAb cetuximab are also listed in the pipeline for several biosimilar developers, but there is no indication of their developmental status as yet and no clinical trials are ongoing in the US.

Sorrento is developing STI-001, a cetuximab biosimilar, and reported that a phase 3 trial had been completed. Instead of a comparison with the reference product, however, the trial compared STI-001 in combination with irinotecan with irinotecan alone. They reported significantly higher ORR, PFS, and OS with the biosimilar compared with irinotecan alone, and a significant increase over historical data with the reference product, as well as fewer side effects and immunogenicity, which they attribute to its manufacture in a different cell line. However, no data has been published and no trials are ongoing in the United States, so the status of its development remains unclear.²⁹
 

Challenges to a robust market

It is an exciting time for biosimilars, with many approvals and drugs being brought to market in the US in the past several years and more poised to follow suit as patents expire. Yet many challenges remain around the growth of a robust biosimilars market.

Several surveys conducted in recent years have demonstrated suboptimal knowledge of all aspects of biosimilars and highlighted the need for evidence-based education across specialties.^30,31 In response, the FDA recently announced that it was launching an educational campaign to further understanding of biosimilars, including naming conventions (Figure 2).^32,33 Numerous other medical professional societies have produced or are in the process of producing biosimilar guidelines.