Combining standard neoadjuvant chemotherapy for locally advanced esophageal cancer with either radiation or docetaxel did not increase the risk of surgical complications, investigators in the JCOG1109 trial reported.

The trial included patients with clinical stage IB, II, or III (non-T4) thoracic esophageal cancer randomly assigned to cisplatin plus 5-fluorouracil (CF), CF plus radiotherapy (CF-RT), or docetaxel plus CF (DCF) prior to surgery.

Results showed the type of therapy did not significantly affect risk for either perioperative complications or deaths. There was also evidence to suggest that a lower risk of postoperative complications with DCF compared with CF might translate into improved prognosis with the addition of docetaxel, said Kazuo Koyanagi, MD, PhD, of National Cancer Center Hospital in Tokyo.

Dr. Koyanagi presented these results at the 2021 Gastrointestinal Cancers Symposium.

“Based on these results, we could say that preoperative chemotherapy with DCF and CF-RT didn’t increase the risk of postoperative complications when compared with standard CF, and whether the decrease in the risk in the DCF would be reflected in the improvement of prognosis should be examined in the future,” Dr. Koyanagi said.
 

Trial details

The JCOG1109 trial is a three-arm, phase 3 trial designed to see whether adding docetaxel or radiation to CF could improve outcomes. In the analysis presented here, the investigators examined whether the choice of regimen could affect the safety of esophagectomy, and they looked for risk factors for postoperative complications.

Patients with histologically proven squamous cell, adenosquamous, or basaloid carcinoma with locally advanced lesions in the thoracic esophagus were eligible.

The patients had to have good performance status (Eastern Cooperative Oncology Group 0 or 1) and could not have had chemotherapy, radiotherapy, or hormonal therapy for any cancer, or prior therapy for esophageal cancer except for complete endoscopic mucosal or submucosal dissection.

A total of 601 patients were enrolled and randomized to receive one of the following treatments:

• CF, with cisplatin at a dose of 80 mg/m² on day 1 and 5-fluorouracil at 800 mg/m² on days 1-5 every 3 weeks for two cycles (199 assigned; 185 had surgery)
• DCF, with cisplatin at 70 mg/m² on day 1, 5-fluorouracil at 750 mg/m² on days 1-5, and docetaxel at 70 mg/m² on day 1 every 3 weeks for three cycles (202 assigned; 183 had surgery)
• CF-RT, with cisplatin at 75 mg/m² on day 1, 5-fluorouracil at 1,000 mg/m² on days 1-4 every 4 weeks for two cycles, plus 1.8 Gy radiation divided into 23 fractions for a total of 41.4 Gy (200 assigned; 178 had surgery).

Patient age, body mass index, tumor location, clinical stage and node status were comparable among the treatment groups.

Operative characteristics (duration, blood loss, approach, extent of lymph node dissection) were generally similar between the arms as well, except that significantly fewer lymph nodes were harvested with CF-RT compared with either CF or DCF (median of 49, 58, and 59, respectively).
 

Results

Incidence rates of major postoperative complications – pneumonia, leakage, and recurrent laryngeal nerve paralysis – were generally similar among the groups.

The cumulative rate of grade 2 or greater postoperative complications was significantly lower for DCF than for CF (P = .02), but not for DCF compared with CF-RT (P = .11). The rates were 43.7% with DCF, 47.8% with CF-RT, and 56.2% with CF.

The rate of grade 2 or greater chylothorax (leakage of lymphatics into the pleural space) was significantly higher with CF-RT than CF (5.1% vs. 1.1%, P = .03) but not with DCF vs. CF (3.8% vs. 1.1%, P = .10)

In multivariable analysis controlling for demographic, clinical, and operative characteristics, factors associated with lower risk for complications included:

• Middle esophageal tumor location vs. upper esophageal tumors (relative risk [RR], 0.79; P = .03)
• DCF (RR, 0.79; P = .02)
• A thoracoscopic vs. open approach (RR, 0.77; P = .002).

The only factor associated with higher risk was operative time longer than 492 minutes (RR, 1.26; P = .008).

Dr. Koyanagi said the reasons for the lower lymph node yield and more frequent chylothorax with CF-RT are unclear but may be related to tissue fibrosis from radiation exposure.
 

CROSS talk

“As a North American surgeon, I generally look to CROSS induction chemotherapy for the majority of my patients for both adenocarcinoma and squamous cell carcinoma of the esophagus,” said invited discussant Jonathan Yeung, MD, PhD, of the Princess Margaret Cancer Centre in Toronto.

The CROSS regimen consists of carboplatin titrated to an area under the curve of 2 mg/mL per minute and paclitaxel at 50 mg/m² for 5 weeks with concurrent radiotherapy to a total dose of 41.4 Gy delivered in 23 fractions, 5 days per week.

Dr. Yeung noted that, of the eligible patients in JCOG1109, 92% of those assigned to DCF actually underwent surgery, and 90% of those assigned to CF-RT went on to surgery, compared with 98% of patients who had surgery in the CROSS trial, suggesting that the DCF and CF-RT regimens may be more toxic.

He also noted that the lower lymph node harvest seen with CF-RT was seen in other studies.

“I must say I’m always impressed by the lymph node yields that our Japanese colleagues can obtain at surgery, but this lower lymph node yield is also borne out in the CROSS data, where there are less lymph nodes harvested following chemoradiotherapy,” he said.

A higher rate of chylothorax with CF-RT was also seen in patients in the CROSS trial who were randomized to receive radiation compared with those who received chemotherapy alone.

“I await the final results to see if there is ultimately better survival,” Dr. Yeung said.

JCOG1109 was supported by grants from the National Cancer Center Research and Development Funds and Agency for Medical Research and Development of Japan. Dr. Koyanagi and Dr. Yeung reported no conflicts of interest.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Combining standard neoadjuvant chemotherapy for locally advanced esophageal cancer with either radiation or docetaxel did not increase the risk of surgical complications, investigators in the JCOG1109 trial reported.

The trial included patients with clinical stage IB, II, or III (non-T4) thoracic esophageal cancer randomly assigned to cisplatin plus 5-fluorouracil (CF), CF plus radiotherapy (CF-RT), or docetaxel plus CF (DCF) prior to surgery.

Results showed the type of therapy did not significantly affect risk for either perioperative complications or deaths. There was also evidence to suggest that a lower risk of postoperative complications with DCF compared with CF might translate into improved prognosis with the addition of docetaxel, said Kazuo Koyanagi, MD, PhD, of National Cancer Center Hospital in Tokyo.

Dr. Koyanagi presented these results at the 2021 Gastrointestinal Cancers Symposium.

“Based on these results, we could say that preoperative chemotherapy with DCF and CF-RT didn’t increase the risk of postoperative complications when compared with standard CF, and whether the decrease in the risk in the DCF would be reflected in the improvement of prognosis should be examined in the future,” Dr. Koyanagi said.
 

Trial details

The JCOG1109 trial is a three-arm, phase 3 trial designed to see whether adding docetaxel or radiation to CF could improve outcomes. In the analysis presented here, the investigators examined whether the choice of regimen could affect the safety of esophagectomy, and they looked for risk factors for postoperative complications.

Patients with histologically proven squamous cell, adenosquamous, or basaloid carcinoma with locally advanced lesions in the thoracic esophagus were eligible.

The patients had to have good performance status (Eastern Cooperative Oncology Group 0 or 1) and could not have had chemotherapy, radiotherapy, or hormonal therapy for any cancer, or prior therapy for esophageal cancer except for complete endoscopic mucosal or submucosal dissection.

A total of 601 patients were enrolled and randomized to receive one of the following treatments:

• CF, with cisplatin at a dose of 80 mg/m² on day 1 and 5-fluorouracil at 800 mg/m² on days 1-5 every 3 weeks for two cycles (199 assigned; 185 had surgery)
• DCF, with cisplatin at 70 mg/m² on day 1, 5-fluorouracil at 750 mg/m² on days 1-5, and docetaxel at 70 mg/m² on day 1 every 3 weeks for three cycles (202 assigned; 183 had surgery)
• CF-RT, with cisplatin at 75 mg/m² on day 1, 5-fluorouracil at 1,000 mg/m² on days 1-4 every 4 weeks for two cycles, plus 1.8 Gy radiation divided into 23 fractions for a total of 41.4 Gy (200 assigned; 178 had surgery).

Patient age, body mass index, tumor location, clinical stage and node status were comparable among the treatment groups.

Operative characteristics (duration, blood loss, approach, extent of lymph node dissection) were generally similar between the arms as well, except that significantly fewer lymph nodes were harvested with CF-RT compared with either CF or DCF (median of 49, 58, and 59, respectively).
 

Results

Incidence rates of major postoperative complications – pneumonia, leakage, and recurrent laryngeal nerve paralysis – were generally similar among the groups.

The cumulative rate of grade 2 or greater postoperative complications was significantly lower for DCF than for CF (P = .02), but not for DCF compared with CF-RT (P = .11). The rates were 43.7% with DCF, 47.8% with CF-RT, and 56.2% with CF.

The rate of grade 2 or greater chylothorax (leakage of lymphatics into the pleural space) was significantly higher with CF-RT than CF (5.1% vs. 1.1%, P = .03) but not with DCF vs. CF (3.8% vs. 1.1%, P = .10)

In multivariable analysis controlling for demographic, clinical, and operative characteristics, factors associated with lower risk for complications included:

• Middle esophageal tumor location vs. upper esophageal tumors (relative risk [RR], 0.79; P = .03)
• DCF (RR, 0.79; P = .02)
• A thoracoscopic vs. open approach (RR, 0.77; P = .002).

The only factor associated with higher risk was operative time longer than 492 minutes (RR, 1.26; P = .008).

Dr. Koyanagi said the reasons for the lower lymph node yield and more frequent chylothorax with CF-RT are unclear but may be related to tissue fibrosis from radiation exposure.
 

CROSS talk

“As a North American surgeon, I generally look to CROSS induction chemotherapy for the majority of my patients for both adenocarcinoma and squamous cell carcinoma of the esophagus,” said invited discussant Jonathan Yeung, MD, PhD, of the Princess Margaret Cancer Centre in Toronto.

The CROSS regimen consists of carboplatin titrated to an area under the curve of 2 mg/mL per minute and paclitaxel at 50 mg/m² for 5 weeks with concurrent radiotherapy to a total dose of 41.4 Gy delivered in 23 fractions, 5 days per week.

Dr. Yeung noted that, of the eligible patients in JCOG1109, 92% of those assigned to DCF actually underwent surgery, and 90% of those assigned to CF-RT went on to surgery, compared with 98% of patients who had surgery in the CROSS trial, suggesting that the DCF and CF-RT regimens may be more toxic.

He also noted that the lower lymph node harvest seen with CF-RT was seen in other studies.

“I must say I’m always impressed by the lymph node yields that our Japanese colleagues can obtain at surgery, but this lower lymph node yield is also borne out in the CROSS data, where there are less lymph nodes harvested following chemoradiotherapy,” he said.

A higher rate of chylothorax with CF-RT was also seen in patients in the CROSS trial who were randomized to receive radiation compared with those who received chemotherapy alone.

“I await the final results to see if there is ultimately better survival,” Dr. Yeung said.

JCOG1109 was supported by grants from the National Cancer Center Research and Development Funds and Agency for Medical Research and Development of Japan. Dr. Koyanagi and Dr. Yeung reported no conflicts of interest.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Combining standard neoadjuvant chemotherapy for locally advanced esophageal cancer with either radiation or docetaxel did not increase the risk of surgical complications, investigators in the JCOG1109 trial reported.

The trial included patients with clinical stage IB, II, or III (non-T4) thoracic esophageal cancer randomly assigned to cisplatin plus 5-fluorouracil (CF), CF plus radiotherapy (CF-RT), or docetaxel plus CF (DCF) prior to surgery.

Results showed the type of therapy did not significantly affect risk for either perioperative complications or deaths. There was also evidence to suggest that a lower risk of postoperative complications with DCF compared with CF might translate into improved prognosis with the addition of docetaxel, said Kazuo Koyanagi, MD, PhD, of National Cancer Center Hospital in Tokyo.

Dr. Koyanagi presented these results at the 2021 Gastrointestinal Cancers Symposium.

“Based on these results, we could say that preoperative chemotherapy with DCF and CF-RT didn’t increase the risk of postoperative complications when compared with standard CF, and whether the decrease in the risk in the DCF would be reflected in the improvement of prognosis should be examined in the future,” Dr. Koyanagi said.
 

Trial details

The JCOG1109 trial is a three-arm, phase 3 trial designed to see whether adding docetaxel or radiation to CF could improve outcomes. In the analysis presented here, the investigators examined whether the choice of regimen could affect the safety of esophagectomy, and they looked for risk factors for postoperative complications.

Patients with histologically proven squamous cell, adenosquamous, or basaloid carcinoma with locally advanced lesions in the thoracic esophagus were eligible.

The patients had to have good performance status (Eastern Cooperative Oncology Group 0 or 1) and could not have had chemotherapy, radiotherapy, or hormonal therapy for any cancer, or prior therapy for esophageal cancer except for complete endoscopic mucosal or submucosal dissection.

A total of 601 patients were enrolled and randomized to receive one of the following treatments:

• CF, with cisplatin at a dose of 80 mg/m² on day 1 and 5-fluorouracil at 800 mg/m² on days 1-5 every 3 weeks for two cycles (199 assigned; 185 had surgery)
• DCF, with cisplatin at 70 mg/m² on day 1, 5-fluorouracil at 750 mg/m² on days 1-5, and docetaxel at 70 mg/m² on day 1 every 3 weeks for three cycles (202 assigned; 183 had surgery)
• CF-RT, with cisplatin at 75 mg/m² on day 1, 5-fluorouracil at 1,000 mg/m² on days 1-4 every 4 weeks for two cycles, plus 1.8 Gy radiation divided into 23 fractions for a total of 41.4 Gy (200 assigned; 178 had surgery).

Patient age, body mass index, tumor location, clinical stage and node status were comparable among the treatment groups.

Operative characteristics (duration, blood loss, approach, extent of lymph node dissection) were generally similar between the arms as well, except that significantly fewer lymph nodes were harvested with CF-RT compared with either CF or DCF (median of 49, 58, and 59, respectively).
 

Results

Incidence rates of major postoperative complications – pneumonia, leakage, and recurrent laryngeal nerve paralysis – were generally similar among the groups.

The cumulative rate of grade 2 or greater postoperative complications was significantly lower for DCF than for CF (P = .02), but not for DCF compared with CF-RT (P = .11). The rates were 43.7% with DCF, 47.8% with CF-RT, and 56.2% with CF.

The rate of grade 2 or greater chylothorax (leakage of lymphatics into the pleural space) was significantly higher with CF-RT than CF (5.1% vs. 1.1%, P = .03) but not with DCF vs. CF (3.8% vs. 1.1%, P = .10)

In multivariable analysis controlling for demographic, clinical, and operative characteristics, factors associated with lower risk for complications included:

• Middle esophageal tumor location vs. upper esophageal tumors (relative risk [RR], 0.79; P = .03)
• DCF (RR, 0.79; P = .02)
• A thoracoscopic vs. open approach (RR, 0.77; P = .002).

The only factor associated with higher risk was operative time longer than 492 minutes (RR, 1.26; P = .008).

Dr. Koyanagi said the reasons for the lower lymph node yield and more frequent chylothorax with CF-RT are unclear but may be related to tissue fibrosis from radiation exposure.
 

CROSS talk

“As a North American surgeon, I generally look to CROSS induction chemotherapy for the majority of my patients for both adenocarcinoma and squamous cell carcinoma of the esophagus,” said invited discussant Jonathan Yeung, MD, PhD, of the Princess Margaret Cancer Centre in Toronto.

The CROSS regimen consists of carboplatin titrated to an area under the curve of 2 mg/mL per minute and paclitaxel at 50 mg/m² for 5 weeks with concurrent radiotherapy to a total dose of 41.4 Gy delivered in 23 fractions, 5 days per week.

Dr. Yeung noted that, of the eligible patients in JCOG1109, 92% of those assigned to DCF actually underwent surgery, and 90% of those assigned to CF-RT went on to surgery, compared with 98% of patients who had surgery in the CROSS trial, suggesting that the DCF and CF-RT regimens may be more toxic.

He also noted that the lower lymph node harvest seen with CF-RT was seen in other studies.

“I must say I’m always impressed by the lymph node yields that our Japanese colleagues can obtain at surgery, but this lower lymph node yield is also borne out in the CROSS data, where there are less lymph nodes harvested following chemoradiotherapy,” he said.

A higher rate of chylothorax with CF-RT was also seen in patients in the CROSS trial who were randomized to receive radiation compared with those who received chemotherapy alone.

“I await the final results to see if there is ultimately better survival,” Dr. Yeung said.

JCOG1109 was supported by grants from the National Cancer Center Research and Development Funds and Agency for Medical Research and Development of Japan. Dr. Koyanagi and Dr. Yeung reported no conflicts of interest.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

Patients with borderline resectable pancreatic ductal adenocarcinoma (PDAC) are often treated with chemotherapy, radiotherapy, or both before undergoing surgery, but the optimal regimen in this setting is controversial.

Results from the Alliance A021501 study suggest the reference regimen should be neoadjuvant therapy with modified FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m², and infusional 5-fluorouracil 2,400 mg/m² over 46 hours), according to Matthew Katz, MD, FACS, chief of the pancreatic surgery service at the University of Texas MD Anderson Cancer Center, Houston.

This regimen improved survival for patients with PDAC, relative to historical data. For patients who received mFOLFIRINOX, the overall 18-month survival rate was 66.4%. However, when this regimen was combined with hypofractionated radiotherapy, the survival benefit was significantly lower, at 47.3%.

These findings were presented at the 2021 Gastrointestinal Cancers Symposium (GICS), which was held online this year.

“ASCO guidelines recommend that preoperative therapy be administered to patients with localized pancreatic adenocarcinoma who have tumors that have a significant radiographic interface with the major mesenteric blood vessels, as these patients are at high risk for a margin-positive operation and short survival when pancreatectomy is performed de novo,” Dr. Katz explained.

Although both chemotherapy and radiotherapy are used in these patients, there is no consensus as to the best approach, he commented.

The goal of Alliance A021501 “was to define a reference preoperative regimen for future trials of preoperative therapy,” he said.

The cohort included 126 patients who were randomly assigned to receive either mFOLFIRINOX (arm A) or mFOLFIRINOX plus radiotherapy (arm B).

Patients in arm A received eight cycles of neoadjuvant mFOLFIRINOX. Patients in arm B received seven cycles of mFOLFIRINOX followed by 5 days of hypofractionated radiotherapy with either stereotactic body radiotherapy or hypofractionated image-guided radiotherapy.

In either arm, patients who did not experience disease progression underwent pancreatectomy followed by four cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², and infusional 5-fluorouracil 2,400 mg/m² over 46 hours).

The study’s primary endpoint was 18-month overall survival in comparison to a historical control of 50%. “An interim futility analysis was scheduled to be conducted following treatment of 30 patients on each arm,” Dr. Katz said. “Either arm in which 11 or fewer patients underwent [curative] R0 resection on protocol was to be declared futile and closed to further enrollment.

“With 62 evaluable patients in each arm, the final efficacy analysis was powered to detect an improvement in 18-month overall survival of 13% over the historical rate of 50%,” said Dr. Katz. “The two arms would be compared only if both were declared efficacious.”

At the interim analysis, 57% of the first 30 patients in arm A had undergone a resection, vs. 33% in arm B. Therefore, arm B was considered futile and was closed to accrual.

The median overall survival in arm A was 29.8 months. The median event-free survival was 15 months. Nearly half (49%) of patients proceeded to pancreatectomy following neoadjuvant therapy. The R0 resection rate was 88%, the pathologic complete response rate was 0%, and the 18-month overall survival rate was 93.1%.

For the patients in arm B, which had been closed to accrual, the median overall survival was 17.1 months, and the median event-free survival was 10.2 months. About one-third (35%) of patients were able to proceed to pancreatectomy. The R0 resection rate was 74%, the pathologic complete response rate was 11%, and the 18-month overall survival rate was 78.9%.

“Preoperative mFOLFIRINOX was associated with favorable overall survival relative to historical criteria in patients with borderline resectable PDAC, and mFOLFIRINOX with radiation therapy met the predefined futility boundary for R0 resection at interim analysis,” Dr. Katz concluded. “Therefore, mFOLFIRINOX represents a reference perioperative regimen for patients with borderline resectable PDAC.”
 

Further investigation needed

The paper’s discussant, Rebecca A. Snyder, MD, MPH, of the Brody School of Medicine, East Carolina University, Greenville, N.C., emphasized that this study was not designed or powered to directly compare chemotherapy alone with chemotherapy plus radiotherapy in the neoadjuvant setting.

She noted that it is surprising that the radiotherapy arm was closed early. She said the reasons for this remain unclear, although a few possible reasons can be speculated.

“Based on multiple studies in both the adjuvant and neoadjuvant setting, including the Alliance [A021501] trial presented today, there is no convincing randomized data that radiation therapy prolongs survival in any population of unselected patients with pancreatic cancer,” said Dr. Snyder.

“Certainly, follow-up questions still remain, specifically regarding the role for non-SBRT radiation in the preoperative setting, which may be answered by the ongoing PREOPANC-2 and PRODIGE 44 trials,” she said.

She added that the “addition of SBRT in the preoperative setting does not appear to be justified.”

The role of radiotherapy for subsets of patients remains unknown, and future investigation should focus on patient-centered endpoints, such as symptomatic local control rates, Dr. Snyder concluded.

The study was funded by the National Institutes of Health. Dr. Katz has had a consulting or advisory role for AbbVie and Alcresta Therapeutics. Dr. Snyder has disclosed no relevant financial relationships.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

A version of this article first appeared on Medscape.com.

Patients with borderline resectable pancreatic ductal adenocarcinoma (PDAC) are often treated with chemotherapy, radiotherapy, or both before undergoing surgery, but the optimal regimen in this setting is controversial.

Results from the Alliance A021501 study suggest the reference regimen should be neoadjuvant therapy with modified FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m², and infusional 5-fluorouracil 2,400 mg/m² over 46 hours), according to Matthew Katz, MD, FACS, chief of the pancreatic surgery service at the University of Texas MD Anderson Cancer Center, Houston.

This regimen improved survival for patients with PDAC, relative to historical data. For patients who received mFOLFIRINOX, the overall 18-month survival rate was 66.4%. However, when this regimen was combined with hypofractionated radiotherapy, the survival benefit was significantly lower, at 47.3%.

These findings were presented at the 2021 Gastrointestinal Cancers Symposium (GICS), which was held online this year.

“ASCO guidelines recommend that preoperative therapy be administered to patients with localized pancreatic adenocarcinoma who have tumors that have a significant radiographic interface with the major mesenteric blood vessels, as these patients are at high risk for a margin-positive operation and short survival when pancreatectomy is performed de novo,” Dr. Katz explained.

Although both chemotherapy and radiotherapy are used in these patients, there is no consensus as to the best approach, he commented.

The goal of Alliance A021501 “was to define a reference preoperative regimen for future trials of preoperative therapy,” he said.

The cohort included 126 patients who were randomly assigned to receive either mFOLFIRINOX (arm A) or mFOLFIRINOX plus radiotherapy (arm B).

Patients in arm A received eight cycles of neoadjuvant mFOLFIRINOX. Patients in arm B received seven cycles of mFOLFIRINOX followed by 5 days of hypofractionated radiotherapy with either stereotactic body radiotherapy or hypofractionated image-guided radiotherapy.

In either arm, patients who did not experience disease progression underwent pancreatectomy followed by four cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², and infusional 5-fluorouracil 2,400 mg/m² over 46 hours).

The study’s primary endpoint was 18-month overall survival in comparison to a historical control of 50%. “An interim futility analysis was scheduled to be conducted following treatment of 30 patients on each arm,” Dr. Katz said. “Either arm in which 11 or fewer patients underwent [curative] R0 resection on protocol was to be declared futile and closed to further enrollment.

“With 62 evaluable patients in each arm, the final efficacy analysis was powered to detect an improvement in 18-month overall survival of 13% over the historical rate of 50%,” said Dr. Katz. “The two arms would be compared only if both were declared efficacious.”

At the interim analysis, 57% of the first 30 patients in arm A had undergone a resection, vs. 33% in arm B. Therefore, arm B was considered futile and was closed to accrual.

The median overall survival in arm A was 29.8 months. The median event-free survival was 15 months. Nearly half (49%) of patients proceeded to pancreatectomy following neoadjuvant therapy. The R0 resection rate was 88%, the pathologic complete response rate was 0%, and the 18-month overall survival rate was 93.1%.

For the patients in arm B, which had been closed to accrual, the median overall survival was 17.1 months, and the median event-free survival was 10.2 months. About one-third (35%) of patients were able to proceed to pancreatectomy. The R0 resection rate was 74%, the pathologic complete response rate was 11%, and the 18-month overall survival rate was 78.9%.

“Preoperative mFOLFIRINOX was associated with favorable overall survival relative to historical criteria in patients with borderline resectable PDAC, and mFOLFIRINOX with radiation therapy met the predefined futility boundary for R0 resection at interim analysis,” Dr. Katz concluded. “Therefore, mFOLFIRINOX represents a reference perioperative regimen for patients with borderline resectable PDAC.”
 

Further investigation needed

The paper’s discussant, Rebecca A. Snyder, MD, MPH, of the Brody School of Medicine, East Carolina University, Greenville, N.C., emphasized that this study was not designed or powered to directly compare chemotherapy alone with chemotherapy plus radiotherapy in the neoadjuvant setting.

She noted that it is surprising that the radiotherapy arm was closed early. She said the reasons for this remain unclear, although a few possible reasons can be speculated.

“Based on multiple studies in both the adjuvant and neoadjuvant setting, including the Alliance [A021501] trial presented today, there is no convincing randomized data that radiation therapy prolongs survival in any population of unselected patients with pancreatic cancer,” said Dr. Snyder.

“Certainly, follow-up questions still remain, specifically regarding the role for non-SBRT radiation in the preoperative setting, which may be answered by the ongoing PREOPANC-2 and PRODIGE 44 trials,” she said.

She added that the “addition of SBRT in the preoperative setting does not appear to be justified.”

The role of radiotherapy for subsets of patients remains unknown, and future investigation should focus on patient-centered endpoints, such as symptomatic local control rates, Dr. Snyder concluded.

The study was funded by the National Institutes of Health. Dr. Katz has had a consulting or advisory role for AbbVie and Alcresta Therapeutics. Dr. Snyder has disclosed no relevant financial relationships.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

A version of this article first appeared on Medscape.com.

Patients with borderline resectable pancreatic ductal adenocarcinoma (PDAC) are often treated with chemotherapy, radiotherapy, or both before undergoing surgery, but the optimal regimen in this setting is controversial.

Results from the Alliance A021501 study suggest the reference regimen should be neoadjuvant therapy with modified FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m², and infusional 5-fluorouracil 2,400 mg/m² over 46 hours), according to Matthew Katz, MD, FACS, chief of the pancreatic surgery service at the University of Texas MD Anderson Cancer Center, Houston.

This regimen improved survival for patients with PDAC, relative to historical data. For patients who received mFOLFIRINOX, the overall 18-month survival rate was 66.4%. However, when this regimen was combined with hypofractionated radiotherapy, the survival benefit was significantly lower, at 47.3%.

These findings were presented at the 2021 Gastrointestinal Cancers Symposium (GICS), which was held online this year.

“ASCO guidelines recommend that preoperative therapy be administered to patients with localized pancreatic adenocarcinoma who have tumors that have a significant radiographic interface with the major mesenteric blood vessels, as these patients are at high risk for a margin-positive operation and short survival when pancreatectomy is performed de novo,” Dr. Katz explained.

Although both chemotherapy and radiotherapy are used in these patients, there is no consensus as to the best approach, he commented.

The goal of Alliance A021501 “was to define a reference preoperative regimen for future trials of preoperative therapy,” he said.

The cohort included 126 patients who were randomly assigned to receive either mFOLFIRINOX (arm A) or mFOLFIRINOX plus radiotherapy (arm B).

Patients in arm A received eight cycles of neoadjuvant mFOLFIRINOX. Patients in arm B received seven cycles of mFOLFIRINOX followed by 5 days of hypofractionated radiotherapy with either stereotactic body radiotherapy or hypofractionated image-guided radiotherapy.

In either arm, patients who did not experience disease progression underwent pancreatectomy followed by four cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², and infusional 5-fluorouracil 2,400 mg/m² over 46 hours).

The study’s primary endpoint was 18-month overall survival in comparison to a historical control of 50%. “An interim futility analysis was scheduled to be conducted following treatment of 30 patients on each arm,” Dr. Katz said. “Either arm in which 11 or fewer patients underwent [curative] R0 resection on protocol was to be declared futile and closed to further enrollment.

“With 62 evaluable patients in each arm, the final efficacy analysis was powered to detect an improvement in 18-month overall survival of 13% over the historical rate of 50%,” said Dr. Katz. “The two arms would be compared only if both were declared efficacious.”

At the interim analysis, 57% of the first 30 patients in arm A had undergone a resection, vs. 33% in arm B. Therefore, arm B was considered futile and was closed to accrual.

The median overall survival in arm A was 29.8 months. The median event-free survival was 15 months. Nearly half (49%) of patients proceeded to pancreatectomy following neoadjuvant therapy. The R0 resection rate was 88%, the pathologic complete response rate was 0%, and the 18-month overall survival rate was 93.1%.

For the patients in arm B, which had been closed to accrual, the median overall survival was 17.1 months, and the median event-free survival was 10.2 months. About one-third (35%) of patients were able to proceed to pancreatectomy. The R0 resection rate was 74%, the pathologic complete response rate was 11%, and the 18-month overall survival rate was 78.9%.

“Preoperative mFOLFIRINOX was associated with favorable overall survival relative to historical criteria in patients with borderline resectable PDAC, and mFOLFIRINOX with radiation therapy met the predefined futility boundary for R0 resection at interim analysis,” Dr. Katz concluded. “Therefore, mFOLFIRINOX represents a reference perioperative regimen for patients with borderline resectable PDAC.”
 

Further investigation needed

The paper’s discussant, Rebecca A. Snyder, MD, MPH, of the Brody School of Medicine, East Carolina University, Greenville, N.C., emphasized that this study was not designed or powered to directly compare chemotherapy alone with chemotherapy plus radiotherapy in the neoadjuvant setting.

She noted that it is surprising that the radiotherapy arm was closed early. She said the reasons for this remain unclear, although a few possible reasons can be speculated.

“Based on multiple studies in both the adjuvant and neoadjuvant setting, including the Alliance [A021501] trial presented today, there is no convincing randomized data that radiation therapy prolongs survival in any population of unselected patients with pancreatic cancer,” said Dr. Snyder.

“Certainly, follow-up questions still remain, specifically regarding the role for non-SBRT radiation in the preoperative setting, which may be answered by the ongoing PREOPANC-2 and PRODIGE 44 trials,” she said.

She added that the “addition of SBRT in the preoperative setting does not appear to be justified.”

The role of radiotherapy for subsets of patients remains unknown, and future investigation should focus on patient-centered endpoints, such as symptomatic local control rates, Dr. Snyder concluded.

The study was funded by the National Institutes of Health. Dr. Katz has had a consulting or advisory role for AbbVie and Alcresta Therapeutics. Dr. Snyder has disclosed no relevant financial relationships.

The Gastrointestinal Cancers Symposium is sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.

A version of this article first appeared on Medscape.com.

Background: It is common practice for providers to intensify antihypertensive regimen during admission for noncardiac conditions even if a patient has a history of well-controlled blood pressure as an outpatient. Many providers have assumed that these changes will benefit patients; however, this outcome had never been studied.

Patients discharged with regimen intensification were more likely to be readmitted (hazard ratio, 1.23; 95% confidence interval, 1.07-1.42; number needed to harm = 27), experience a medication-related serious adverse event (HR, 1.42; 95% CI, 1.06-1.88; NNH = 63), and have a cardiovascular event (HR, 1.65; 95% CI, 1.13-2.4) within 30 days of discharge. At 1 year, no significant difference in mortality, cardiovascular events, or systolic BP were noted between the two groups.

A subgroup analysis of patients with poorly controlled blood pressure as outpatients (defined as systolic blood pressure greater than 140 mm Hg) who had their anti-hypertensive medications intensified did not show significant difference in 30-day readmission, severe adverse events, or cardiovascular events.

Limitations of the study include observational design and majority male sex (97.5%) of the study population.

Bottom line: Intensification of antihypertensive regimen among older adults hospitalized for noncardiac conditions with well-controlled blood pressure as an outpatient can potentially cause harm.

Citation: Anderson TS et al. Clinical outcomes after intensifying antihypertensive medication regimens among older adults at hospital discharge. JAMA Intern Med. 2019 Aug 19. doi: 10.1001/jamainternmed.2019.3007.

Dr. Zarookian is a hospitalist at Maine Medical Center in Portland and Stephens Memorial Hospital in Norway, Maine.

Background: It is common practice for providers to intensify antihypertensive regimen during admission for noncardiac conditions even if a patient has a history of well-controlled blood pressure as an outpatient. Many providers have assumed that these changes will benefit patients; however, this outcome had never been studied.

Patients discharged with regimen intensification were more likely to be readmitted (hazard ratio, 1.23; 95% confidence interval, 1.07-1.42; number needed to harm = 27), experience a medication-related serious adverse event (HR, 1.42; 95% CI, 1.06-1.88; NNH = 63), and have a cardiovascular event (HR, 1.65; 95% CI, 1.13-2.4) within 30 days of discharge. At 1 year, no significant difference in mortality, cardiovascular events, or systolic BP were noted between the two groups.

A subgroup analysis of patients with poorly controlled blood pressure as outpatients (defined as systolic blood pressure greater than 140 mm Hg) who had their anti-hypertensive medications intensified did not show significant difference in 30-day readmission, severe adverse events, or cardiovascular events.

Limitations of the study include observational design and majority male sex (97.5%) of the study population.

Bottom line: Intensification of antihypertensive regimen among older adults hospitalized for noncardiac conditions with well-controlled blood pressure as an outpatient can potentially cause harm.

Citation: Anderson TS et al. Clinical outcomes after intensifying antihypertensive medication regimens among older adults at hospital discharge. JAMA Intern Med. 2019 Aug 19. doi: 10.1001/jamainternmed.2019.3007.

Dr. Zarookian is a hospitalist at Maine Medical Center in Portland and Stephens Memorial Hospital in Norway, Maine.

Background: It is common practice for providers to intensify antihypertensive regimen during admission for noncardiac conditions even if a patient has a history of well-controlled blood pressure as an outpatient. Many providers have assumed that these changes will benefit patients; however, this outcome had never been studied.

Patients discharged with regimen intensification were more likely to be readmitted (hazard ratio, 1.23; 95% confidence interval, 1.07-1.42; number needed to harm = 27), experience a medication-related serious adverse event (HR, 1.42; 95% CI, 1.06-1.88; NNH = 63), and have a cardiovascular event (HR, 1.65; 95% CI, 1.13-2.4) within 30 days of discharge. At 1 year, no significant difference in mortality, cardiovascular events, or systolic BP were noted between the two groups.

A subgroup analysis of patients with poorly controlled blood pressure as outpatients (defined as systolic blood pressure greater than 140 mm Hg) who had their anti-hypertensive medications intensified did not show significant difference in 30-day readmission, severe adverse events, or cardiovascular events.

Limitations of the study include observational design and majority male sex (97.5%) of the study population.

Bottom line: Intensification of antihypertensive regimen among older adults hospitalized for noncardiac conditions with well-controlled blood pressure as an outpatient can potentially cause harm.

Citation: Anderson TS et al. Clinical outcomes after intensifying antihypertensive medication regimens among older adults at hospital discharge. JAMA Intern Med. 2019 Aug 19. doi: 10.1001/jamainternmed.2019.3007.

Dr. Zarookian is a hospitalist at Maine Medical Center in Portland and Stephens Memorial Hospital in Norway, Maine.

It’s in the nature of presidential candidates and new presidents to promise big things. Just months after his 1961 inauguration, President John F. Kennedy vowed to send a man to the moon by the end of the decade. That pledge was kept, but many others haven’t been, such as candidate Bill Clinton’s promise to provide universal health care and presidential hopeful George H.W. Bush’s guarantee of no new taxes.

Now, during a once-in-a-century pandemic, incoming President Joe Biden has promised to provide 100 million COVID-19 vaccinations in his first 100 days in office.

“This team will help get … at least 100 million covid vaccine shots into the arms of the American people in the first 100 days,” Biden said during a Dec. 8 news conference introducing key members of his health team.

When first asked about his pledge, the Biden team said the president-elect meant 50 million people would get their two-dose regimen. The incoming administration has since updated this plan, saying it will release vaccine doses as soon as they’re available instead of holding back some of that supply for second doses.

Either way, Biden may run into difficulty meeting that 100 million mark.

“I think it’s an attainable goal. I think it’s going to be extremely challenging,” said Claire Hannan, executive director of the Association of Immunization Managers.

While a pace of 1 million doses a day is “somewhat of an increase over what we’re already doing,” a much higher rate of vaccinations will be necessary to stem the pandemic, said Larry Levitt, executive vice president for health policy at Kaiser Family Foundation. (KHN is an editorially independent program of KFF.) “The Biden administration has plans to rationalize vaccine distribution, but increasing the supply quickly” could be a difficult task.

Under the Trump administration, vaccine deployment has been much slower than Biden’s plan. The rollout began on Dec. 14. Since then, 12 million shots have been given and 31 million doses have been shipped out, according to the Centers for Disease Control and Prevention’s vaccine tracker.

This sluggishness has been attributed to a lack of communication between the federal government and state and local health departments, not enough funding for large-scale vaccination efforts, and confusing federal guidance on distribution of the vaccines.

The same problems could plague the Biden administration, said experts.

States still aren’t sure how much vaccine they’ll get and whether there will be a sufficient supply, said Dr. Marcus Plescia, chief medical officer for the Association of State and Territorial Health Officials, which represents state public health agencies.

“We have been given little information about the amount of vaccine the states will receive in the near future and are of the impression that there may not be 1 million doses available per day in the first 100 days of the Biden administration,” said Dr. Plescia. “Or at least not in the early stages of the 100 days.”

Another challenge has been a lack of funding. Public health departments have had to start vaccination campaigns while also operating testing centers and conducting contact tracing efforts with budgets that have been critically underfunded for years.

“States have to pay for creating the systems, identifying the personnel, training, staffing, tracking people, information campaigns – all the things that go into getting a shot in someone’s arm,” said Jennifer Kates, director of global health & HIV policy at KFF. “They’re having to create an unprecedented mass vaccination program on a shaky foundation.”

The latest covid stimulus bill, signed into law in December, allocates almost $9 billion in funding to the CDC for vaccination efforts. About $4.5 billion is supposed to go to states, territories and tribal organizations, and $3 billion of that is slated to arrive soon.

But it’s not clear that level of funding can sustain mass vaccination campaigns as more groups become eligible for the vaccine.

Biden released a $1.9 trillion plan last week to address covid and the struggling economy. It includes $160 billion to create national vaccination and testing programs, but also earmarks funds for $1,400 stimulus payments to individuals, state and local government aid, extension of unemployment insurance, and financial assistance for schools to reopen safely.

Though it took Congress almost eight months to pass the last covid relief bill after Republican objections to the cost, Biden seems optimistic he’ll get some Republicans on board for his plan. But it’s not yet clear that will work.

There’s also the question of whether outgoing President Donald Trump’s impeachment trial will get in the way of Biden’s legislative priorities.

In addition, states have complained about a lack of guidance and confusing instructions on which groups should be given priority status for vaccination, an issue the Biden administration will need to address.

On Dec. 3, the CDC recommended health care personnel, residents of long-term care facilities, those 75 and older, and front-line essential workers should be immunized first. But on Jan. 12, the CDC shifted course and recommended that everyone over age 65 should be immunized. In a speech Biden gave on Jan. 15 detailing his vaccination plan, he said he would stick to the CDC’s recommendation to prioritize those over 65.

Outgoing Health and Human Services Secretary Alex Azar also said on Jan. 12 that states that moved their vaccine supply fastest would be prioritized in getting more shipments. It’s not known yet whether the Biden administration’s CDC will stick to this guidance. Critics have said it could make vaccine distribution less equitable.

In general, taking over with a strong vision and clear communication will be key to ramping up vaccine distribution, said Ms. Hannan.

“Everyone needs to understand what the goal is and how it’s going to work,” she said.

A challenge for Biden will be tamping expectations that the vaccine is all that is needed to end the pandemic. Across the country, covid cases are higher than ever, and in many locations officials cannot control the spread.

Public health experts said Biden must amp up efforts to increase testing across the country, as he has suggested he will do by promising to establish a national pandemic testing board.

With so much focus on vaccine distribution, it’s important that this part of the equation not be lost. Right now, “it’s completely all over the map,” said KFF’s Ms. Kates, adding that the federal government will need a “good sense” of who is and is not being tested in different areas in order to “fix” public health capacity.

Jan. 20, 2021, marks the launch of The Biden Promise Tracker, which monitors the 100 most important campaign promises of President Joseph R. Biden. Biden listed the coronavirus and a variety of other health-related issues among his top priorities. You can see the entire list – including improving the economy, responding to calls for racial justice and combating climate change – here. As part of KHN’s partnership with PolitiFact, we will follow the health-related issues and then rate them on whether the promise was achieved: Promise Kept, Promise Broken, Compromise, Stalled, In the Works or Not Yet Rated. We rate the promise not on the president’s intentions or effort, but on verifiable outcomes. PolitiFact previously tracked the promises of President Donald Trump and President Barack Obama. 

 

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of KFF, which is not affiliated with Kaiser Permanente.

It’s in the nature of presidential candidates and new presidents to promise big things. Just months after his 1961 inauguration, President John F. Kennedy vowed to send a man to the moon by the end of the decade. That pledge was kept, but many others haven’t been, such as candidate Bill Clinton’s promise to provide universal health care and presidential hopeful George H.W. Bush’s guarantee of no new taxes.

Now, during a once-in-a-century pandemic, incoming President Joe Biden has promised to provide 100 million COVID-19 vaccinations in his first 100 days in office.

“This team will help get … at least 100 million covid vaccine shots into the arms of the American people in the first 100 days,” Biden said during a Dec. 8 news conference introducing key members of his health team.

When first asked about his pledge, the Biden team said the president-elect meant 50 million people would get their two-dose regimen. The incoming administration has since updated this plan, saying it will release vaccine doses as soon as they’re available instead of holding back some of that supply for second doses.

Either way, Biden may run into difficulty meeting that 100 million mark.

“I think it’s an attainable goal. I think it’s going to be extremely challenging,” said Claire Hannan, executive director of the Association of Immunization Managers.

While a pace of 1 million doses a day is “somewhat of an increase over what we’re already doing,” a much higher rate of vaccinations will be necessary to stem the pandemic, said Larry Levitt, executive vice president for health policy at Kaiser Family Foundation. (KHN is an editorially independent program of KFF.) “The Biden administration has plans to rationalize vaccine distribution, but increasing the supply quickly” could be a difficult task.

Under the Trump administration, vaccine deployment has been much slower than Biden’s plan. The rollout began on Dec. 14. Since then, 12 million shots have been given and 31 million doses have been shipped out, according to the Centers for Disease Control and Prevention’s vaccine tracker.

This sluggishness has been attributed to a lack of communication between the federal government and state and local health departments, not enough funding for large-scale vaccination efforts, and confusing federal guidance on distribution of the vaccines.

The same problems could plague the Biden administration, said experts.

States still aren’t sure how much vaccine they’ll get and whether there will be a sufficient supply, said Dr. Marcus Plescia, chief medical officer for the Association of State and Territorial Health Officials, which represents state public health agencies.

“We have been given little information about the amount of vaccine the states will receive in the near future and are of the impression that there may not be 1 million doses available per day in the first 100 days of the Biden administration,” said Dr. Plescia. “Or at least not in the early stages of the 100 days.”

Another challenge has been a lack of funding. Public health departments have had to start vaccination campaigns while also operating testing centers and conducting contact tracing efforts with budgets that have been critically underfunded for years.

“States have to pay for creating the systems, identifying the personnel, training, staffing, tracking people, information campaigns – all the things that go into getting a shot in someone’s arm,” said Jennifer Kates, director of global health & HIV policy at KFF. “They’re having to create an unprecedented mass vaccination program on a shaky foundation.”

The latest covid stimulus bill, signed into law in December, allocates almost $9 billion in funding to the CDC for vaccination efforts. About $4.5 billion is supposed to go to states, territories and tribal organizations, and $3 billion of that is slated to arrive soon.

But it’s not clear that level of funding can sustain mass vaccination campaigns as more groups become eligible for the vaccine.

Biden released a $1.9 trillion plan last week to address covid and the struggling economy. It includes $160 billion to create national vaccination and testing programs, but also earmarks funds for $1,400 stimulus payments to individuals, state and local government aid, extension of unemployment insurance, and financial assistance for schools to reopen safely.

Though it took Congress almost eight months to pass the last covid relief bill after Republican objections to the cost, Biden seems optimistic he’ll get some Republicans on board for his plan. But it’s not yet clear that will work.

There’s also the question of whether outgoing President Donald Trump’s impeachment trial will get in the way of Biden’s legislative priorities.

In addition, states have complained about a lack of guidance and confusing instructions on which groups should be given priority status for vaccination, an issue the Biden administration will need to address.

On Dec. 3, the CDC recommended health care personnel, residents of long-term care facilities, those 75 and older, and front-line essential workers should be immunized first. But on Jan. 12, the CDC shifted course and recommended that everyone over age 65 should be immunized. In a speech Biden gave on Jan. 15 detailing his vaccination plan, he said he would stick to the CDC’s recommendation to prioritize those over 65.

Outgoing Health and Human Services Secretary Alex Azar also said on Jan. 12 that states that moved their vaccine supply fastest would be prioritized in getting more shipments. It’s not known yet whether the Biden administration’s CDC will stick to this guidance. Critics have said it could make vaccine distribution less equitable.

In general, taking over with a strong vision and clear communication will be key to ramping up vaccine distribution, said Ms. Hannan.

“Everyone needs to understand what the goal is and how it’s going to work,” she said.

A challenge for Biden will be tamping expectations that the vaccine is all that is needed to end the pandemic. Across the country, covid cases are higher than ever, and in many locations officials cannot control the spread.

Public health experts said Biden must amp up efforts to increase testing across the country, as he has suggested he will do by promising to establish a national pandemic testing board.

With so much focus on vaccine distribution, it’s important that this part of the equation not be lost. Right now, “it’s completely all over the map,” said KFF’s Ms. Kates, adding that the federal government will need a “good sense” of who is and is not being tested in different areas in order to “fix” public health capacity.

Jan. 20, 2021, marks the launch of The Biden Promise Tracker, which monitors the 100 most important campaign promises of President Joseph R. Biden. Biden listed the coronavirus and a variety of other health-related issues among his top priorities. You can see the entire list – including improving the economy, responding to calls for racial justice and combating climate change – here. As part of KHN’s partnership with PolitiFact, we will follow the health-related issues and then rate them on whether the promise was achieved: Promise Kept, Promise Broken, Compromise, Stalled, In the Works or Not Yet Rated. We rate the promise not on the president’s intentions or effort, but on verifiable outcomes. PolitiFact previously tracked the promises of President Donald Trump and President Barack Obama. 

 

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of KFF, which is not affiliated with Kaiser Permanente.

It’s in the nature of presidential candidates and new presidents to promise big things. Just months after his 1961 inauguration, President John F. Kennedy vowed to send a man to the moon by the end of the decade. That pledge was kept, but many others haven’t been, such as candidate Bill Clinton’s promise to provide universal health care and presidential hopeful George H.W. Bush’s guarantee of no new taxes.

Now, during a once-in-a-century pandemic, incoming President Joe Biden has promised to provide 100 million COVID-19 vaccinations in his first 100 days in office.

“This team will help get … at least 100 million covid vaccine shots into the arms of the American people in the first 100 days,” Biden said during a Dec. 8 news conference introducing key members of his health team.

When first asked about his pledge, the Biden team said the president-elect meant 50 million people would get their two-dose regimen. The incoming administration has since updated this plan, saying it will release vaccine doses as soon as they’re available instead of holding back some of that supply for second doses.

Either way, Biden may run into difficulty meeting that 100 million mark.

“I think it’s an attainable goal. I think it’s going to be extremely challenging,” said Claire Hannan, executive director of the Association of Immunization Managers.

While a pace of 1 million doses a day is “somewhat of an increase over what we’re already doing,” a much higher rate of vaccinations will be necessary to stem the pandemic, said Larry Levitt, executive vice president for health policy at Kaiser Family Foundation. (KHN is an editorially independent program of KFF.) “The Biden administration has plans to rationalize vaccine distribution, but increasing the supply quickly” could be a difficult task.

Under the Trump administration, vaccine deployment has been much slower than Biden’s plan. The rollout began on Dec. 14. Since then, 12 million shots have been given and 31 million doses have been shipped out, according to the Centers for Disease Control and Prevention’s vaccine tracker.

This sluggishness has been attributed to a lack of communication between the federal government and state and local health departments, not enough funding for large-scale vaccination efforts, and confusing federal guidance on distribution of the vaccines.

The same problems could plague the Biden administration, said experts.

States still aren’t sure how much vaccine they’ll get and whether there will be a sufficient supply, said Dr. Marcus Plescia, chief medical officer for the Association of State and Territorial Health Officials, which represents state public health agencies.

“We have been given little information about the amount of vaccine the states will receive in the near future and are of the impression that there may not be 1 million doses available per day in the first 100 days of the Biden administration,” said Dr. Plescia. “Or at least not in the early stages of the 100 days.”

Another challenge has been a lack of funding. Public health departments have had to start vaccination campaigns while also operating testing centers and conducting contact tracing efforts with budgets that have been critically underfunded for years.

“States have to pay for creating the systems, identifying the personnel, training, staffing, tracking people, information campaigns – all the things that go into getting a shot in someone’s arm,” said Jennifer Kates, director of global health & HIV policy at KFF. “They’re having to create an unprecedented mass vaccination program on a shaky foundation.”

The latest covid stimulus bill, signed into law in December, allocates almost $9 billion in funding to the CDC for vaccination efforts. About $4.5 billion is supposed to go to states, territories and tribal organizations, and $3 billion of that is slated to arrive soon.

But it’s not clear that level of funding can sustain mass vaccination campaigns as more groups become eligible for the vaccine.

Biden released a $1.9 trillion plan last week to address covid and the struggling economy. It includes $160 billion to create national vaccination and testing programs, but also earmarks funds for $1,400 stimulus payments to individuals, state and local government aid, extension of unemployment insurance, and financial assistance for schools to reopen safely.

Though it took Congress almost eight months to pass the last covid relief bill after Republican objections to the cost, Biden seems optimistic he’ll get some Republicans on board for his plan. But it’s not yet clear that will work.

There’s also the question of whether outgoing President Donald Trump’s impeachment trial will get in the way of Biden’s legislative priorities.

In addition, states have complained about a lack of guidance and confusing instructions on which groups should be given priority status for vaccination, an issue the Biden administration will need to address.

On Dec. 3, the CDC recommended health care personnel, residents of long-term care facilities, those 75 and older, and front-line essential workers should be immunized first. But on Jan. 12, the CDC shifted course and recommended that everyone over age 65 should be immunized. In a speech Biden gave on Jan. 15 detailing his vaccination plan, he said he would stick to the CDC’s recommendation to prioritize those over 65.

Outgoing Health and Human Services Secretary Alex Azar also said on Jan. 12 that states that moved their vaccine supply fastest would be prioritized in getting more shipments. It’s not known yet whether the Biden administration’s CDC will stick to this guidance. Critics have said it could make vaccine distribution less equitable.

In general, taking over with a strong vision and clear communication will be key to ramping up vaccine distribution, said Ms. Hannan.

“Everyone needs to understand what the goal is and how it’s going to work,” she said.

A challenge for Biden will be tamping expectations that the vaccine is all that is needed to end the pandemic. Across the country, covid cases are higher than ever, and in many locations officials cannot control the spread.

Public health experts said Biden must amp up efforts to increase testing across the country, as he has suggested he will do by promising to establish a national pandemic testing board.

With so much focus on vaccine distribution, it’s important that this part of the equation not be lost. Right now, “it’s completely all over the map,” said KFF’s Ms. Kates, adding that the federal government will need a “good sense” of who is and is not being tested in different areas in order to “fix” public health capacity.

Jan. 20, 2021, marks the launch of The Biden Promise Tracker, which monitors the 100 most important campaign promises of President Joseph R. Biden. Biden listed the coronavirus and a variety of other health-related issues among his top priorities. You can see the entire list – including improving the economy, responding to calls for racial justice and combating climate change – here. As part of KHN’s partnership with PolitiFact, we will follow the health-related issues and then rate them on whether the promise was achieved: Promise Kept, Promise Broken, Compromise, Stalled, In the Works or Not Yet Rated. We rate the promise not on the president’s intentions or effort, but on verifiable outcomes. PolitiFact previously tracked the promises of President Donald Trump and President Barack Obama. 

 

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of KFF, which is not affiliated with Kaiser Permanente.

Many emergency medicine (EM) physicians who responded to a Medscape survey said they have treated COVID-19 patients without appropriate personal protective equipment (PPE).

In the Medscape Emergency Medicine Physicians’ COVID-19 Experience Report, 21% of respondents said that that was sometimes the case; 7% said that it was often the case; and 1% said they always treat patients without appropriate PPE.

EM physicians were the physicians most likely to treat COVID-19 patients in person.

Steep income drops

Survey authors wrote that two-thirds of EM physicians have experienced income loss during the pandemic. Most (71%) saw their income drop by between 11% and 50%; 11% saw a decrease of more than 50%. Among other specialties, the percentages of those who have experienced a drop of more than 50% are far higher. Among ophthalmologists, 51% said they had experienced such a drop; among allergists, 46%; plastic surgeons, 46%; and otolaryngologists, 45%.

Asked whether their burnout levels have increased in the wake of COVID-19, 74% of EM physicians said burnout had intensified; 23% reported no change; and 3% said burnout had lessened.

Reports of loneliness have been widespread during the pandemic, owing to stay-at-home orders and social distancing. More EM physicians than physicians in general said feelings of loneliness had increased for them in the past year.

More than half of EM doctors (55%) said they are experiencing more loneliness in the pandemic, compared with 46% of all physicians who felt that way; 42% said those feelings have not changed; and 3% said they have been less lonely.
 

Grief and stress relief

Fewer than half (42%) of the respondents reported that their workplace offers clinician activities to help with grief and stress; 39% said their workplace didn’t offer such help; and 19% said they were unsure.

The percentages were nearly identical to the percentages of physicians overall who answered whether their workplace offered help for grief and stress.

Along with insecurity regarding physical and mental health, COVID-19 has introduced more questions about financial health. Here’s a look at how emergency physicians said they would change the way they save and spend.

Challenges to daily practice

By the time this survey was taken, a large percentage of patients had delayed or avoided urgent or routine medical care for reasons related to COVID-19, so survey authors asked whether EM physicians’ patient population had changed.

Survey authors wrote that “most EM physicians (82%) are seeing patients with non-COVID diseases, such as cardiovascular problems or diabetes, who otherwise probably would have sought treatment earlier.”

COVID-19 has also thrown a major obstacle into most EM physicians’ careers by preventing them from doing the job to the best of their ability. That loss is one of the three primary components of burnout.

More than two-thirds (67%) said COVID-19 has hampered their ability to be as good a doctor as they would like.

A version of this article first appeared on Medscape.com.

Many emergency medicine (EM) physicians who responded to a Medscape survey said they have treated COVID-19 patients without appropriate personal protective equipment (PPE).

In the Medscape Emergency Medicine Physicians’ COVID-19 Experience Report, 21% of respondents said that that was sometimes the case; 7% said that it was often the case; and 1% said they always treat patients without appropriate PPE.

EM physicians were the physicians most likely to treat COVID-19 patients in person.

Steep income drops

Survey authors wrote that two-thirds of EM physicians have experienced income loss during the pandemic. Most (71%) saw their income drop by between 11% and 50%; 11% saw a decrease of more than 50%. Among other specialties, the percentages of those who have experienced a drop of more than 50% are far higher. Among ophthalmologists, 51% said they had experienced such a drop; among allergists, 46%; plastic surgeons, 46%; and otolaryngologists, 45%.

Asked whether their burnout levels have increased in the wake of COVID-19, 74% of EM physicians said burnout had intensified; 23% reported no change; and 3% said burnout had lessened.

Reports of loneliness have been widespread during the pandemic, owing to stay-at-home orders and social distancing. More EM physicians than physicians in general said feelings of loneliness had increased for them in the past year.

More than half of EM doctors (55%) said they are experiencing more loneliness in the pandemic, compared with 46% of all physicians who felt that way; 42% said those feelings have not changed; and 3% said they have been less lonely.
 

Grief and stress relief

Fewer than half (42%) of the respondents reported that their workplace offers clinician activities to help with grief and stress; 39% said their workplace didn’t offer such help; and 19% said they were unsure.

The percentages were nearly identical to the percentages of physicians overall who answered whether their workplace offered help for grief and stress.

Along with insecurity regarding physical and mental health, COVID-19 has introduced more questions about financial health. Here’s a look at how emergency physicians said they would change the way they save and spend.

Challenges to daily practice

By the time this survey was taken, a large percentage of patients had delayed or avoided urgent or routine medical care for reasons related to COVID-19, so survey authors asked whether EM physicians’ patient population had changed.

Survey authors wrote that “most EM physicians (82%) are seeing patients with non-COVID diseases, such as cardiovascular problems or diabetes, who otherwise probably would have sought treatment earlier.”

COVID-19 has also thrown a major obstacle into most EM physicians’ careers by preventing them from doing the job to the best of their ability. That loss is one of the three primary components of burnout.

More than two-thirds (67%) said COVID-19 has hampered their ability to be as good a doctor as they would like.

A version of this article first appeared on Medscape.com.

Many emergency medicine (EM) physicians who responded to a Medscape survey said they have treated COVID-19 patients without appropriate personal protective equipment (PPE).

In the Medscape Emergency Medicine Physicians’ COVID-19 Experience Report, 21% of respondents said that that was sometimes the case; 7% said that it was often the case; and 1% said they always treat patients without appropriate PPE.

EM physicians were the physicians most likely to treat COVID-19 patients in person.

Steep income drops

Survey authors wrote that two-thirds of EM physicians have experienced income loss during the pandemic. Most (71%) saw their income drop by between 11% and 50%; 11% saw a decrease of more than 50%. Among other specialties, the percentages of those who have experienced a drop of more than 50% are far higher. Among ophthalmologists, 51% said they had experienced such a drop; among allergists, 46%; plastic surgeons, 46%; and otolaryngologists, 45%.

Asked whether their burnout levels have increased in the wake of COVID-19, 74% of EM physicians said burnout had intensified; 23% reported no change; and 3% said burnout had lessened.

Reports of loneliness have been widespread during the pandemic, owing to stay-at-home orders and social distancing. More EM physicians than physicians in general said feelings of loneliness had increased for them in the past year.

More than half of EM doctors (55%) said they are experiencing more loneliness in the pandemic, compared with 46% of all physicians who felt that way; 42% said those feelings have not changed; and 3% said they have been less lonely.
 

Grief and stress relief

Fewer than half (42%) of the respondents reported that their workplace offers clinician activities to help with grief and stress; 39% said their workplace didn’t offer such help; and 19% said they were unsure.

The percentages were nearly identical to the percentages of physicians overall who answered whether their workplace offered help for grief and stress.

Along with insecurity regarding physical and mental health, COVID-19 has introduced more questions about financial health. Here’s a look at how emergency physicians said they would change the way they save and spend.

Challenges to daily practice

By the time this survey was taken, a large percentage of patients had delayed or avoided urgent or routine medical care for reasons related to COVID-19, so survey authors asked whether EM physicians’ patient population had changed.

Survey authors wrote that “most EM physicians (82%) are seeing patients with non-COVID diseases, such as cardiovascular problems or diabetes, who otherwise probably would have sought treatment earlier.”

COVID-19 has also thrown a major obstacle into most EM physicians’ careers by preventing them from doing the job to the best of their ability. That loss is one of the three primary components of burnout.

More than two-thirds (67%) said COVID-19 has hampered their ability to be as good a doctor as they would like.

A version of this article first appeared on Medscape.com.

A one-stop shop approach to managing the spectrum of complications in patients with type 2 diabetes with a coordinated, multidisciplinary team of clinicians has taken root in at least two U.S. medical centers, and their efforts have now joined to take this concept national through the Cardiometabolic Center Alliance, which hopes to have at least 20 such centers running by the end of 2022.

Doug Brunk/MDedge News

In patients with type 2 diabetes (T2D), “multiple organs are affected by the same disease process,” notably the heart, kidneys, vasculature, and liver, but the care these patients often receive today is “fragmented, and typically without good coordination,” explained Mikhail N. Kosiborod, MD, a cardiologist and codirector of the Saint Luke’s Michael & Marlys Haverty Cardiometabolic Center of Excellence in Kansas City, Mo.

“We need to depart from the outdated idea that each medical specialty focuses on an organ system. It’s one patient with one disease that affects multiple organs and needs comprehensive, multidisciplinary care,” he said.

Historically, “we’ve looked to primary care physicians to ‘conduct the orchestra’ for complex, multispecialty care” for patients with T2D, but a recent “avalanche” of new treatments with new data and recommendations has made coordination by a single, generalist physician essentially impossible. “It isn’t realistic” to expect a single primary care physician to coordinate all the care a patient with T2D now needs to receive, said Dr. Kosiborod, who is also a professor of medicine at the University of Missouri–Kansas City. Plus, “patients can get lost” when they try to navigate on their own among several physicians, possibly in disparate locations, and without fully understanding what each physician is responsible for managing.
 

Application of recommended treatments ‘lagging’

“The data are there, and the recommendations are there for T2D and cardiovascular disease, heart failure, and diabetic kidney disease, but the problem has been implementation,” said Dr. Kosiborod. “Application in practice is lagging way behind the recommendations.” That led him and his associates to devise a “new model of care for patients with T2D,” the cardiometabolic center (CMC), as a status quo alternative.

The CMC paradigm is that patients with T2D, especially those with existing cardiovascular or chronic kidney disease or at high risk for these complications, undergo assessment and treatment at one site from a multidisciplinary staff of physicians and allied caregivers including nurse practitioners, nurse coordinators, pharmacists, dieticians, and diabetes educators who are cross-trained for managing both T2D and cardiovascular diseases.

The Cardiometabolic Center Alliance builds on the idea that this care model is defined by a set of detailed treatment protocols and processes of care that other sites can adopt to boost the number of patients aided by this approach, to gather data from a larger patient pool in a dedicated registry to better document the program’s impact, and to form a quality-improvement network that can collectively improve performance.

“It’s absolutely replicable,” maintained Dr. Kosiborod, who is also executive director of the Cardiometabolic Center Alliance. “We’ve codified all of the care and medications into an impressive package. We now have something that works, and many other centers are interested in building programs like this. By establishing a base of well-defined protocols and operating procedures we can train a cadre of allied professionals who can effectively implement the program across wider populations of patients, while using the brick and mortar center to manage more complex patients,” he added.

“We’re not taking patients” from primary care physicians, Dr. Kosiborod stressed. “We’re helping generalists give better care. They already have their hands full. We’re here to help physicians do better.”

He cited a recent study of 1,735 patients with atherosclerotic cardiovascular disease and diabetes (96% with T2D) enrolled in a registry at 119 U.S. sites during 2016-2018 that found less than 7% were on the full range of guideline-directed medical therapy that they qualified for based on existing treatment guidelines. “This is not acceptable,” Dr. Kosiborod declared.

“It’s so obvious that this needs to be a combined approach. It’s very difficult to have one provider take care of all of the T2D complications. There needs to be a new approach, and [the Cardiometabolic Center program at Saint Luke’s] has done a great job getting their initiative underway to take a more global approach,” commented Ralph A. DeFronzo, MD, chief of the diabetes division and professor of medicine at the University of Texas Health Science Center, San Antonio.
 

Early results show improved metrics

The Saint Luke’s Haverty CMC launched in 2019, and data from its first 129 patients with at least one follow-up visit documented early efficacy for the program, as reported at the American Heart Association’s Quality of Care and Outcome’s Research meeting, held virtually on May 15 and 16, 2020.

That analysis from Dr. Kosiborod and associates compared various short-term metrics among their CMC patients against a control cohort of 387 similar patients with T2D who also received care in the Saint Luke’s Health System during 2019 but outside of the CMC. This observational study involved no patient randomization, but the researchers used propensity scoring to match the control patients with those managed in the CMC by several demographic and clinical parameters.

During follow-up that was generally less than 6 months, patients managed in the CMC averaged 12 pounds of weight loss, a 0.5% reduction in their average hemoglobin A1c, a mean 4.6–mm Hg cut in their systolic blood pressure, an average drop in their LDL cholesterol of 11.4 mg/dL, and among those receiving insulin the daily, average insulin dose fell by a relative 43%, compared with baseline. Among the controls, averages for these five parameters were weight loss of 2 pounds, a cut in A1c of 0.2%, a systolic blood pressure reduction of 0.6 mm Hg, a drop in LDL cholesterol of 4.9 mg/dL, and a relative rise in insulin dose of 6%. All of these between group differences were statistically significant except for LDL cholesterol.

Additional analysis of the medications that patients in the CMC and control group received also showed striking differences. Combined prescriptions for all components of guideline-directed medical therapy went to 41% of the CMC patients, compared with 2% of the controls, a statistically significant difference. Contributing to this difference were significantly increased rates of prescriptions for ACE inhibitors and statins.

The CMC staff also started 57% of their patients on a SGLT2 inhibitor and 90% on a GLP-1 receptor agonist (GLP-1 RA), compared with rates of 18% and 13%, respectively, among controls. Both of these between-group differences were also significant, and they highlighted the willingness and success of the CMC clinicians to put a large number of their patients on agents from both of these beneficial drug classes. This is a notable change from usual recent practice that limits most patients who actually receive these medications to a drug from just one of these two classes, often because of real or perceived limits on insurance coverage.

The data from these initial patients in the Saint Luke’s CMC show that the program was “very successful; it looks very promising,” said Dr. Kosiborod. The results show “transformational improvement in the quality of care.” Subsequent to this initial cohort from 2019, the Saint Luke’s CMC has seen “hundreds” of additional patients with T2D.
 

The Cardiometabolic Center Alliance gets started

The second member of the Cardiometabolic Center Alliance is a program run by the University Hospitals system based in Cleveland that had begun earlier in 2020. The University Hospitals’ Center for Integrated and Novel Approaches in Vascular-Metabolic Disease (CINEMA) uses a comprehensive, multidisciplinary-care model developed independently of but very similar to the Saint Luke’s CMC. By the end of 2020, the CINEMA program had managed about 150 patients, said Sanjay Rajagopalan, MD, director of CINEMA and a professor of medicine at Case Western Reserve University, Cleveland.

“Our outcomes have been quite similar” to what the Saint Luke’s program reported, he said. “We had better use of guideline-directed therapies, more weight loss, and better control of metabolic parameters.” The CINEMA program entered the Cardiometabolic Center Alliance as a “key strategic partner,” which means it will have a role in shaping the alliance going forward. One issue the alliance faces is how to leverage its growth to improve management of patients with T2D who do not have access to a CMC.

The CMCs “are not meant for every patient with T2D, but for those with high risk for cardiovascular complications who require extra attention,” Dr. Rajagopalan said in an interview. Both he and Dr. Kosiborod acknowledged that, even if 200 CMCs were to eventually open, and even if each center averaged 5,000 managed patients, those 1 million patients would be a small fraction of the total number of U.S. patients with T2D.

“Having these centers will produce a ripple effect. The protocols will percolate to primary care physicians,” Dr. Rajagopalan predicted. Once that happens, “not all patients will need to go to a cardiometabolic center.” In addition, leveraging established protocols via nurse coordinators and virtual care could bring this model to many more patients, Dr. Kosiborod noted.

By the end of 2020, a total of three additional U.S. centers had joined Saint Luke’s and University Hospitals in the alliance, but Dr. Kosiborod said that none of the three had yet been officially announced. The alliance has also started a national cardiometabolic registry, which will be “instrumental for its mission to track, benchmark, and improve quality of care and outcomes; enable mechanisms for “learning health care systems”; and can be used to answer important research questions,” Dr. Kosiborod said.

Combined SGLT2 inhibitor and GLP-1 RA treatment takes off

A key element of the more aggressive, risk-driven management emphasized in the CMC approach is frequent use of combined treatment with an SGLT2 inhibitor and a GLP-1 RA. Both classes of glucose-lowering drugs have well-documented, risk-reducing benefits, notably reduced atherosclerotic cardiovascular events and weight loss produced by the GLP1-RAs, and cuts in heart failure onset and hospitalizations and slowing of chronic kidney disease progression by the SGLT2 inhibitors.

Until now, medical society recommendations as well as opinion leaders have approached these two drug classes with a presumption that physicians would usually prescribe patients an agent from only one of these two classes, largely because the high cost of agents in both classes, all still under patent, often means coverage limits by insurers. Physicians at both the Saint Luke’s and University Hospitals programs have been more proactive, and successful, in prescribing agents from both classes to their high-risk patients with T2D.

“We use combination treatment quite a bit,” said Dr. Kosiborod. “It’s very sensible to use both. Their mechanisms of action are different and likely don’t overlap, so it’s reasonable to presume their activity is complimentary.” But he acknowledged that this has not yet been formally studied for cardiovascular or renal outcomes. Study results have documented complimentary effects between the two classes for weight loss, blood pressure reduction, and to some extent A1c reduction. A key reason for more frequent combined treatment with an SGLT2 inhibitor and GLP-1 RA is increased focus on the ability of both drug classes to lower risk in patients with T2D and high cardiovascular-disease risk, rather than prescribing decisions driven largely by trying to further reduce a patient’s A1c.

Although insurance coverage is not a given, the Saint Luke’s CMC has had good results using patient-assistance programs run by various drug companies. Some patients have received their medications free of charge or with modest copays, depending on their income and insurance coverage. At Saint Luke’s, “many” patients with T2D have been able to get free medications through assistance programs, he said. And for patients with health insurance, getting coverage for an agent from each class “is easier now than it was 3-4 years ago.”

Dr. Kosiborod has been a consultant to several companies, and has received research grants from AstraZeneca and Boehringer Ingelheim. Dr. DeFronzo received research grants from Astra Zeneca, Janssen, and Merck; he has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, and Novo Nordisk; and he has been a speaker on behalf of AstraZeneca and Novo Nordisk. Dr. Rajagopalan has been a consultant to Novo Nordisk and Takeda.

[email protected]

A one-stop shop approach to managing the spectrum of complications in patients with type 2 diabetes with a coordinated, multidisciplinary team of clinicians has taken root in at least two U.S. medical centers, and their efforts have now joined to take this concept national through the Cardiometabolic Center Alliance, which hopes to have at least 20 such centers running by the end of 2022.

Doug Brunk/MDedge News

In patients with type 2 diabetes (T2D), “multiple organs are affected by the same disease process,” notably the heart, kidneys, vasculature, and liver, but the care these patients often receive today is “fragmented, and typically without good coordination,” explained Mikhail N. Kosiborod, MD, a cardiologist and codirector of the Saint Luke’s Michael & Marlys Haverty Cardiometabolic Center of Excellence in Kansas City, Mo.

“We need to depart from the outdated idea that each medical specialty focuses on an organ system. It’s one patient with one disease that affects multiple organs and needs comprehensive, multidisciplinary care,” he said.

Historically, “we’ve looked to primary care physicians to ‘conduct the orchestra’ for complex, multispecialty care” for patients with T2D, but a recent “avalanche” of new treatments with new data and recommendations has made coordination by a single, generalist physician essentially impossible. “It isn’t realistic” to expect a single primary care physician to coordinate all the care a patient with T2D now needs to receive, said Dr. Kosiborod, who is also a professor of medicine at the University of Missouri–Kansas City. Plus, “patients can get lost” when they try to navigate on their own among several physicians, possibly in disparate locations, and without fully understanding what each physician is responsible for managing.
 

Application of recommended treatments ‘lagging’

“The data are there, and the recommendations are there for T2D and cardiovascular disease, heart failure, and diabetic kidney disease, but the problem has been implementation,” said Dr. Kosiborod. “Application in practice is lagging way behind the recommendations.” That led him and his associates to devise a “new model of care for patients with T2D,” the cardiometabolic center (CMC), as a status quo alternative.

The CMC paradigm is that patients with T2D, especially those with existing cardiovascular or chronic kidney disease or at high risk for these complications, undergo assessment and treatment at one site from a multidisciplinary staff of physicians and allied caregivers including nurse practitioners, nurse coordinators, pharmacists, dieticians, and diabetes educators who are cross-trained for managing both T2D and cardiovascular diseases.

The Cardiometabolic Center Alliance builds on the idea that this care model is defined by a set of detailed treatment protocols and processes of care that other sites can adopt to boost the number of patients aided by this approach, to gather data from a larger patient pool in a dedicated registry to better document the program’s impact, and to form a quality-improvement network that can collectively improve performance.

“It’s absolutely replicable,” maintained Dr. Kosiborod, who is also executive director of the Cardiometabolic Center Alliance. “We’ve codified all of the care and medications into an impressive package. We now have something that works, and many other centers are interested in building programs like this. By establishing a base of well-defined protocols and operating procedures we can train a cadre of allied professionals who can effectively implement the program across wider populations of patients, while using the brick and mortar center to manage more complex patients,” he added.

“We’re not taking patients” from primary care physicians, Dr. Kosiborod stressed. “We’re helping generalists give better care. They already have their hands full. We’re here to help physicians do better.”

He cited a recent study of 1,735 patients with atherosclerotic cardiovascular disease and diabetes (96% with T2D) enrolled in a registry at 119 U.S. sites during 2016-2018 that found less than 7% were on the full range of guideline-directed medical therapy that they qualified for based on existing treatment guidelines. “This is not acceptable,” Dr. Kosiborod declared.

“It’s so obvious that this needs to be a combined approach. It’s very difficult to have one provider take care of all of the T2D complications. There needs to be a new approach, and [the Cardiometabolic Center program at Saint Luke’s] has done a great job getting their initiative underway to take a more global approach,” commented Ralph A. DeFronzo, MD, chief of the diabetes division and professor of medicine at the University of Texas Health Science Center, San Antonio.
 

Early results show improved metrics

The Saint Luke’s Haverty CMC launched in 2019, and data from its first 129 patients with at least one follow-up visit documented early efficacy for the program, as reported at the American Heart Association’s Quality of Care and Outcome’s Research meeting, held virtually on May 15 and 16, 2020.

That analysis from Dr. Kosiborod and associates compared various short-term metrics among their CMC patients against a control cohort of 387 similar patients with T2D who also received care in the Saint Luke’s Health System during 2019 but outside of the CMC. This observational study involved no patient randomization, but the researchers used propensity scoring to match the control patients with those managed in the CMC by several demographic and clinical parameters.

During follow-up that was generally less than 6 months, patients managed in the CMC averaged 12 pounds of weight loss, a 0.5% reduction in their average hemoglobin A1c, a mean 4.6–mm Hg cut in their systolic blood pressure, an average drop in their LDL cholesterol of 11.4 mg/dL, and among those receiving insulin the daily, average insulin dose fell by a relative 43%, compared with baseline. Among the controls, averages for these five parameters were weight loss of 2 pounds, a cut in A1c of 0.2%, a systolic blood pressure reduction of 0.6 mm Hg, a drop in LDL cholesterol of 4.9 mg/dL, and a relative rise in insulin dose of 6%. All of these between group differences were statistically significant except for LDL cholesterol.

Additional analysis of the medications that patients in the CMC and control group received also showed striking differences. Combined prescriptions for all components of guideline-directed medical therapy went to 41% of the CMC patients, compared with 2% of the controls, a statistically significant difference. Contributing to this difference were significantly increased rates of prescriptions for ACE inhibitors and statins.

The CMC staff also started 57% of their patients on a SGLT2 inhibitor and 90% on a GLP-1 receptor agonist (GLP-1 RA), compared with rates of 18% and 13%, respectively, among controls. Both of these between-group differences were also significant, and they highlighted the willingness and success of the CMC clinicians to put a large number of their patients on agents from both of these beneficial drug classes. This is a notable change from usual recent practice that limits most patients who actually receive these medications to a drug from just one of these two classes, often because of real or perceived limits on insurance coverage.

The data from these initial patients in the Saint Luke’s CMC show that the program was “very successful; it looks very promising,” said Dr. Kosiborod. The results show “transformational improvement in the quality of care.” Subsequent to this initial cohort from 2019, the Saint Luke’s CMC has seen “hundreds” of additional patients with T2D.
 

The Cardiometabolic Center Alliance gets started

The second member of the Cardiometabolic Center Alliance is a program run by the University Hospitals system based in Cleveland that had begun earlier in 2020. The University Hospitals’ Center for Integrated and Novel Approaches in Vascular-Metabolic Disease (CINEMA) uses a comprehensive, multidisciplinary-care model developed independently of but very similar to the Saint Luke’s CMC. By the end of 2020, the CINEMA program had managed about 150 patients, said Sanjay Rajagopalan, MD, director of CINEMA and a professor of medicine at Case Western Reserve University, Cleveland.

“Our outcomes have been quite similar” to what the Saint Luke’s program reported, he said. “We had better use of guideline-directed therapies, more weight loss, and better control of metabolic parameters.” The CINEMA program entered the Cardiometabolic Center Alliance as a “key strategic partner,” which means it will have a role in shaping the alliance going forward. One issue the alliance faces is how to leverage its growth to improve management of patients with T2D who do not have access to a CMC.

The CMCs “are not meant for every patient with T2D, but for those with high risk for cardiovascular complications who require extra attention,” Dr. Rajagopalan said in an interview. Both he and Dr. Kosiborod acknowledged that, even if 200 CMCs were to eventually open, and even if each center averaged 5,000 managed patients, those 1 million patients would be a small fraction of the total number of U.S. patients with T2D.

“Having these centers will produce a ripple effect. The protocols will percolate to primary care physicians,” Dr. Rajagopalan predicted. Once that happens, “not all patients will need to go to a cardiometabolic center.” In addition, leveraging established protocols via nurse coordinators and virtual care could bring this model to many more patients, Dr. Kosiborod noted.

By the end of 2020, a total of three additional U.S. centers had joined Saint Luke’s and University Hospitals in the alliance, but Dr. Kosiborod said that none of the three had yet been officially announced. The alliance has also started a national cardiometabolic registry, which will be “instrumental for its mission to track, benchmark, and improve quality of care and outcomes; enable mechanisms for “learning health care systems”; and can be used to answer important research questions,” Dr. Kosiborod said.

Combined SGLT2 inhibitor and GLP-1 RA treatment takes off

A key element of the more aggressive, risk-driven management emphasized in the CMC approach is frequent use of combined treatment with an SGLT2 inhibitor and a GLP-1 RA. Both classes of glucose-lowering drugs have well-documented, risk-reducing benefits, notably reduced atherosclerotic cardiovascular events and weight loss produced by the GLP1-RAs, and cuts in heart failure onset and hospitalizations and slowing of chronic kidney disease progression by the SGLT2 inhibitors.

Until now, medical society recommendations as well as opinion leaders have approached these two drug classes with a presumption that physicians would usually prescribe patients an agent from only one of these two classes, largely because the high cost of agents in both classes, all still under patent, often means coverage limits by insurers. Physicians at both the Saint Luke’s and University Hospitals programs have been more proactive, and successful, in prescribing agents from both classes to their high-risk patients with T2D.

“We use combination treatment quite a bit,” said Dr. Kosiborod. “It’s very sensible to use both. Their mechanisms of action are different and likely don’t overlap, so it’s reasonable to presume their activity is complimentary.” But he acknowledged that this has not yet been formally studied for cardiovascular or renal outcomes. Study results have documented complimentary effects between the two classes for weight loss, blood pressure reduction, and to some extent A1c reduction. A key reason for more frequent combined treatment with an SGLT2 inhibitor and GLP-1 RA is increased focus on the ability of both drug classes to lower risk in patients with T2D and high cardiovascular-disease risk, rather than prescribing decisions driven largely by trying to further reduce a patient’s A1c.

Although insurance coverage is not a given, the Saint Luke’s CMC has had good results using patient-assistance programs run by various drug companies. Some patients have received their medications free of charge or with modest copays, depending on their income and insurance coverage. At Saint Luke’s, “many” patients with T2D have been able to get free medications through assistance programs, he said. And for patients with health insurance, getting coverage for an agent from each class “is easier now than it was 3-4 years ago.”

Dr. Kosiborod has been a consultant to several companies, and has received research grants from AstraZeneca and Boehringer Ingelheim. Dr. DeFronzo received research grants from Astra Zeneca, Janssen, and Merck; he has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, and Novo Nordisk; and he has been a speaker on behalf of AstraZeneca and Novo Nordisk. Dr. Rajagopalan has been a consultant to Novo Nordisk and Takeda.

[email protected]

A one-stop shop approach to managing the spectrum of complications in patients with type 2 diabetes with a coordinated, multidisciplinary team of clinicians has taken root in at least two U.S. medical centers, and their efforts have now joined to take this concept national through the Cardiometabolic Center Alliance, which hopes to have at least 20 such centers running by the end of 2022.

Doug Brunk/MDedge News

In patients with type 2 diabetes (T2D), “multiple organs are affected by the same disease process,” notably the heart, kidneys, vasculature, and liver, but the care these patients often receive today is “fragmented, and typically without good coordination,” explained Mikhail N. Kosiborod, MD, a cardiologist and codirector of the Saint Luke’s Michael & Marlys Haverty Cardiometabolic Center of Excellence in Kansas City, Mo.

“We need to depart from the outdated idea that each medical specialty focuses on an organ system. It’s one patient with one disease that affects multiple organs and needs comprehensive, multidisciplinary care,” he said.

Historically, “we’ve looked to primary care physicians to ‘conduct the orchestra’ for complex, multispecialty care” for patients with T2D, but a recent “avalanche” of new treatments with new data and recommendations has made coordination by a single, generalist physician essentially impossible. “It isn’t realistic” to expect a single primary care physician to coordinate all the care a patient with T2D now needs to receive, said Dr. Kosiborod, who is also a professor of medicine at the University of Missouri–Kansas City. Plus, “patients can get lost” when they try to navigate on their own among several physicians, possibly in disparate locations, and without fully understanding what each physician is responsible for managing.
 

Application of recommended treatments ‘lagging’

“The data are there, and the recommendations are there for T2D and cardiovascular disease, heart failure, and diabetic kidney disease, but the problem has been implementation,” said Dr. Kosiborod. “Application in practice is lagging way behind the recommendations.” That led him and his associates to devise a “new model of care for patients with T2D,” the cardiometabolic center (CMC), as a status quo alternative.

The CMC paradigm is that patients with T2D, especially those with existing cardiovascular or chronic kidney disease or at high risk for these complications, undergo assessment and treatment at one site from a multidisciplinary staff of physicians and allied caregivers including nurse practitioners, nurse coordinators, pharmacists, dieticians, and diabetes educators who are cross-trained for managing both T2D and cardiovascular diseases.

The Cardiometabolic Center Alliance builds on the idea that this care model is defined by a set of detailed treatment protocols and processes of care that other sites can adopt to boost the number of patients aided by this approach, to gather data from a larger patient pool in a dedicated registry to better document the program’s impact, and to form a quality-improvement network that can collectively improve performance.

“It’s absolutely replicable,” maintained Dr. Kosiborod, who is also executive director of the Cardiometabolic Center Alliance. “We’ve codified all of the care and medications into an impressive package. We now have something that works, and many other centers are interested in building programs like this. By establishing a base of well-defined protocols and operating procedures we can train a cadre of allied professionals who can effectively implement the program across wider populations of patients, while using the brick and mortar center to manage more complex patients,” he added.

“We’re not taking patients” from primary care physicians, Dr. Kosiborod stressed. “We’re helping generalists give better care. They already have their hands full. We’re here to help physicians do better.”

He cited a recent study of 1,735 patients with atherosclerotic cardiovascular disease and diabetes (96% with T2D) enrolled in a registry at 119 U.S. sites during 2016-2018 that found less than 7% were on the full range of guideline-directed medical therapy that they qualified for based on existing treatment guidelines. “This is not acceptable,” Dr. Kosiborod declared.

“It’s so obvious that this needs to be a combined approach. It’s very difficult to have one provider take care of all of the T2D complications. There needs to be a new approach, and [the Cardiometabolic Center program at Saint Luke’s] has done a great job getting their initiative underway to take a more global approach,” commented Ralph A. DeFronzo, MD, chief of the diabetes division and professor of medicine at the University of Texas Health Science Center, San Antonio.
 

Early results show improved metrics

The Saint Luke’s Haverty CMC launched in 2019, and data from its first 129 patients with at least one follow-up visit documented early efficacy for the program, as reported at the American Heart Association’s Quality of Care and Outcome’s Research meeting, held virtually on May 15 and 16, 2020.

That analysis from Dr. Kosiborod and associates compared various short-term metrics among their CMC patients against a control cohort of 387 similar patients with T2D who also received care in the Saint Luke’s Health System during 2019 but outside of the CMC. This observational study involved no patient randomization, but the researchers used propensity scoring to match the control patients with those managed in the CMC by several demographic and clinical parameters.

During follow-up that was generally less than 6 months, patients managed in the CMC averaged 12 pounds of weight loss, a 0.5% reduction in their average hemoglobin A1c, a mean 4.6–mm Hg cut in their systolic blood pressure, an average drop in their LDL cholesterol of 11.4 mg/dL, and among those receiving insulin the daily, average insulin dose fell by a relative 43%, compared with baseline. Among the controls, averages for these five parameters were weight loss of 2 pounds, a cut in A1c of 0.2%, a systolic blood pressure reduction of 0.6 mm Hg, a drop in LDL cholesterol of 4.9 mg/dL, and a relative rise in insulin dose of 6%. All of these between group differences were statistically significant except for LDL cholesterol.

Additional analysis of the medications that patients in the CMC and control group received also showed striking differences. Combined prescriptions for all components of guideline-directed medical therapy went to 41% of the CMC patients, compared with 2% of the controls, a statistically significant difference. Contributing to this difference were significantly increased rates of prescriptions for ACE inhibitors and statins.

The CMC staff also started 57% of their patients on a SGLT2 inhibitor and 90% on a GLP-1 receptor agonist (GLP-1 RA), compared with rates of 18% and 13%, respectively, among controls. Both of these between-group differences were also significant, and they highlighted the willingness and success of the CMC clinicians to put a large number of their patients on agents from both of these beneficial drug classes. This is a notable change from usual recent practice that limits most patients who actually receive these medications to a drug from just one of these two classes, often because of real or perceived limits on insurance coverage.

The data from these initial patients in the Saint Luke’s CMC show that the program was “very successful; it looks very promising,” said Dr. Kosiborod. The results show “transformational improvement in the quality of care.” Subsequent to this initial cohort from 2019, the Saint Luke’s CMC has seen “hundreds” of additional patients with T2D.
 

The Cardiometabolic Center Alliance gets started

The second member of the Cardiometabolic Center Alliance is a program run by the University Hospitals system based in Cleveland that had begun earlier in 2020. The University Hospitals’ Center for Integrated and Novel Approaches in Vascular-Metabolic Disease (CINEMA) uses a comprehensive, multidisciplinary-care model developed independently of but very similar to the Saint Luke’s CMC. By the end of 2020, the CINEMA program had managed about 150 patients, said Sanjay Rajagopalan, MD, director of CINEMA and a professor of medicine at Case Western Reserve University, Cleveland.

“Our outcomes have been quite similar” to what the Saint Luke’s program reported, he said. “We had better use of guideline-directed therapies, more weight loss, and better control of metabolic parameters.” The CINEMA program entered the Cardiometabolic Center Alliance as a “key strategic partner,” which means it will have a role in shaping the alliance going forward. One issue the alliance faces is how to leverage its growth to improve management of patients with T2D who do not have access to a CMC.

The CMCs “are not meant for every patient with T2D, but for those with high risk for cardiovascular complications who require extra attention,” Dr. Rajagopalan said in an interview. Both he and Dr. Kosiborod acknowledged that, even if 200 CMCs were to eventually open, and even if each center averaged 5,000 managed patients, those 1 million patients would be a small fraction of the total number of U.S. patients with T2D.

“Having these centers will produce a ripple effect. The protocols will percolate to primary care physicians,” Dr. Rajagopalan predicted. Once that happens, “not all patients will need to go to a cardiometabolic center.” In addition, leveraging established protocols via nurse coordinators and virtual care could bring this model to many more patients, Dr. Kosiborod noted.

By the end of 2020, a total of three additional U.S. centers had joined Saint Luke’s and University Hospitals in the alliance, but Dr. Kosiborod said that none of the three had yet been officially announced. The alliance has also started a national cardiometabolic registry, which will be “instrumental for its mission to track, benchmark, and improve quality of care and outcomes; enable mechanisms for “learning health care systems”; and can be used to answer important research questions,” Dr. Kosiborod said.

Combined SGLT2 inhibitor and GLP-1 RA treatment takes off

A key element of the more aggressive, risk-driven management emphasized in the CMC approach is frequent use of combined treatment with an SGLT2 inhibitor and a GLP-1 RA. Both classes of glucose-lowering drugs have well-documented, risk-reducing benefits, notably reduced atherosclerotic cardiovascular events and weight loss produced by the GLP1-RAs, and cuts in heart failure onset and hospitalizations and slowing of chronic kidney disease progression by the SGLT2 inhibitors.

Until now, medical society recommendations as well as opinion leaders have approached these two drug classes with a presumption that physicians would usually prescribe patients an agent from only one of these two classes, largely because the high cost of agents in both classes, all still under patent, often means coverage limits by insurers. Physicians at both the Saint Luke’s and University Hospitals programs have been more proactive, and successful, in prescribing agents from both classes to their high-risk patients with T2D.

“We use combination treatment quite a bit,” said Dr. Kosiborod. “It’s very sensible to use both. Their mechanisms of action are different and likely don’t overlap, so it’s reasonable to presume their activity is complimentary.” But he acknowledged that this has not yet been formally studied for cardiovascular or renal outcomes. Study results have documented complimentary effects between the two classes for weight loss, blood pressure reduction, and to some extent A1c reduction. A key reason for more frequent combined treatment with an SGLT2 inhibitor and GLP-1 RA is increased focus on the ability of both drug classes to lower risk in patients with T2D and high cardiovascular-disease risk, rather than prescribing decisions driven largely by trying to further reduce a patient’s A1c.

Although insurance coverage is not a given, the Saint Luke’s CMC has had good results using patient-assistance programs run by various drug companies. Some patients have received their medications free of charge or with modest copays, depending on their income and insurance coverage. At Saint Luke’s, “many” patients with T2D have been able to get free medications through assistance programs, he said. And for patients with health insurance, getting coverage for an agent from each class “is easier now than it was 3-4 years ago.”

Dr. Kosiborod has been a consultant to several companies, and has received research grants from AstraZeneca and Boehringer Ingelheim. Dr. DeFronzo received research grants from Astra Zeneca, Janssen, and Merck; he has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, Janssen, and Novo Nordisk; and he has been a speaker on behalf of AstraZeneca and Novo Nordisk. Dr. Rajagopalan has been a consultant to Novo Nordisk and Takeda.

[email protected]

Finding the current domestic and global situations too disheartening to write about, I have decided for the moment to take the long view in hopes of finding something to stimulate your imaginations. It appears that we have several vaccines effective against SARS-CoV-2 if not in your hands at the moment at least in someone’s freezer or at the very least somewhere near beginning of their journey in the production pipeline. It may be a year of more but thanks to the vaccines and herd immunity there will be a time when parents may feel more comfortable about bringing their children into your office. How are you going to dial back your office routine to something even vaguely familiar?

To keep your office afloat financially you have probably been forced to adopt and adapt telemedicine strategies to your practice style. Prior to the pandemic you may have been among the few who were actively experimenting with practicing remotely. But, it is more likely that you had given little serious thought to how you would manage your patients without them being physically present.

You probably carried in your mind a list of symptoms and complaints which you had promised yourself that you would never treat without first laying eyes and hands on the patient. You may have even codified this list into a set of guidelines that you included in the office manual for your nurses, assistants, and receptionists. You may have looked askance at some of your colleagues whom you felt too often treated their patients (and yours when they were covering) based on what seemed to be scanty information gleaned from a phone call. The impropriety of this kind of clinical behavior may have even come up at staff meetings or at least been the topic of hallway discussions.

How did your list of complaints that demanded an in-person visit evolve? I suspect that in large part it was formed as you modeled the behavior of your mentors and teachers. In some cases you may have heard of tragic cases in which a child had died or suffered serious consequences of being treated without an in-person evaluation. In many cases you were following a tradition or ethic that said treating in certain circumstances without an exam just wasn’t done.

Have the realities of the pandemic forced you to alter your list of must-see-before-I’ll-treat complaints? Have you found yourself calling in antibiotic prescriptions for children with ear pain who 1 year ago you would have told to come in for an office visit? Are you treating “strep throats” without a rapid strep test or culture? How many stimulant prescriptions have you refilled for children who haven’t been reevaluated in the office in over a year? How are you going to manage the tsunami of requests for sports physicals once the junior high and high school teams are allowed to return to action? You probably won’t have the time to examine all of the sports candidates who show up in your office with crumpled forms recently retrieved from crumb-filled backpacks.

Where are you going to reset the bar as the pandemic lifts and the barriers that have prevented patients from coming to your office over the last year or year and a half recede? Have you realized that many of your office visits in prepandemic times were unnecessary? How many children with otitis really needed to be followed up with an ear recheck visit? Which children with sore throats and a fever needed to be examined? Was a yearly exam really necessary for a high school sophomore who wanted to play basketball? Has your comfort zone widened to include more patient complaints that can be managed without a face to face encounter? Where will telemedicine fit into the mix?

At some time in the next 12 months you will have to recalibrate and reset the bar. It will probably be a gradual process that in large part can be molded by the responses of the families who may have also come to realize that seeing you in the office isn’t quite as necessary as you both may have thought it was.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected]

Finding the current domestic and global situations too disheartening to write about, I have decided for the moment to take the long view in hopes of finding something to stimulate your imaginations. It appears that we have several vaccines effective against SARS-CoV-2 if not in your hands at the moment at least in someone’s freezer or at the very least somewhere near beginning of their journey in the production pipeline. It may be a year of more but thanks to the vaccines and herd immunity there will be a time when parents may feel more comfortable about bringing their children into your office. How are you going to dial back your office routine to something even vaguely familiar?

To keep your office afloat financially you have probably been forced to adopt and adapt telemedicine strategies to your practice style. Prior to the pandemic you may have been among the few who were actively experimenting with practicing remotely. But, it is more likely that you had given little serious thought to how you would manage your patients without them being physically present.

You probably carried in your mind a list of symptoms and complaints which you had promised yourself that you would never treat without first laying eyes and hands on the patient. You may have even codified this list into a set of guidelines that you included in the office manual for your nurses, assistants, and receptionists. You may have looked askance at some of your colleagues whom you felt too often treated their patients (and yours when they were covering) based on what seemed to be scanty information gleaned from a phone call. The impropriety of this kind of clinical behavior may have even come up at staff meetings or at least been the topic of hallway discussions.

How did your list of complaints that demanded an in-person visit evolve? I suspect that in large part it was formed as you modeled the behavior of your mentors and teachers. In some cases you may have heard of tragic cases in which a child had died or suffered serious consequences of being treated without an in-person evaluation. In many cases you were following a tradition or ethic that said treating in certain circumstances without an exam just wasn’t done.

Have the realities of the pandemic forced you to alter your list of must-see-before-I’ll-treat complaints? Have you found yourself calling in antibiotic prescriptions for children with ear pain who 1 year ago you would have told to come in for an office visit? Are you treating “strep throats” without a rapid strep test or culture? How many stimulant prescriptions have you refilled for children who haven’t been reevaluated in the office in over a year? How are you going to manage the tsunami of requests for sports physicals once the junior high and high school teams are allowed to return to action? You probably won’t have the time to examine all of the sports candidates who show up in your office with crumpled forms recently retrieved from crumb-filled backpacks.

Where are you going to reset the bar as the pandemic lifts and the barriers that have prevented patients from coming to your office over the last year or year and a half recede? Have you realized that many of your office visits in prepandemic times were unnecessary? How many children with otitis really needed to be followed up with an ear recheck visit? Which children with sore throats and a fever needed to be examined? Was a yearly exam really necessary for a high school sophomore who wanted to play basketball? Has your comfort zone widened to include more patient complaints that can be managed without a face to face encounter? Where will telemedicine fit into the mix?

At some time in the next 12 months you will have to recalibrate and reset the bar. It will probably be a gradual process that in large part can be molded by the responses of the families who may have also come to realize that seeing you in the office isn’t quite as necessary as you both may have thought it was.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected]

Finding the current domestic and global situations too disheartening to write about, I have decided for the moment to take the long view in hopes of finding something to stimulate your imaginations. It appears that we have several vaccines effective against SARS-CoV-2 if not in your hands at the moment at least in someone’s freezer or at the very least somewhere near beginning of their journey in the production pipeline. It may be a year of more but thanks to the vaccines and herd immunity there will be a time when parents may feel more comfortable about bringing their children into your office. How are you going to dial back your office routine to something even vaguely familiar?

To keep your office afloat financially you have probably been forced to adopt and adapt telemedicine strategies to your practice style. Prior to the pandemic you may have been among the few who were actively experimenting with practicing remotely. But, it is more likely that you had given little serious thought to how you would manage your patients without them being physically present.

You probably carried in your mind a list of symptoms and complaints which you had promised yourself that you would never treat without first laying eyes and hands on the patient. You may have even codified this list into a set of guidelines that you included in the office manual for your nurses, assistants, and receptionists. You may have looked askance at some of your colleagues whom you felt too often treated their patients (and yours when they were covering) based on what seemed to be scanty information gleaned from a phone call. The impropriety of this kind of clinical behavior may have even come up at staff meetings or at least been the topic of hallway discussions.

How did your list of complaints that demanded an in-person visit evolve? I suspect that in large part it was formed as you modeled the behavior of your mentors and teachers. In some cases you may have heard of tragic cases in which a child had died or suffered serious consequences of being treated without an in-person evaluation. In many cases you were following a tradition or ethic that said treating in certain circumstances without an exam just wasn’t done.

Have the realities of the pandemic forced you to alter your list of must-see-before-I’ll-treat complaints? Have you found yourself calling in antibiotic prescriptions for children with ear pain who 1 year ago you would have told to come in for an office visit? Are you treating “strep throats” without a rapid strep test or culture? How many stimulant prescriptions have you refilled for children who haven’t been reevaluated in the office in over a year? How are you going to manage the tsunami of requests for sports physicals once the junior high and high school teams are allowed to return to action? You probably won’t have the time to examine all of the sports candidates who show up in your office with crumpled forms recently retrieved from crumb-filled backpacks.

Where are you going to reset the bar as the pandemic lifts and the barriers that have prevented patients from coming to your office over the last year or year and a half recede? Have you realized that many of your office visits in prepandemic times were unnecessary? How many children with otitis really needed to be followed up with an ear recheck visit? Which children with sore throats and a fever needed to be examined? Was a yearly exam really necessary for a high school sophomore who wanted to play basketball? Has your comfort zone widened to include more patient complaints that can be managed without a face to face encounter? Where will telemedicine fit into the mix?

At some time in the next 12 months you will have to recalibrate and reset the bar. It will probably be a gradual process that in large part can be molded by the responses of the families who may have also come to realize that seeing you in the office isn’t quite as necessary as you both may have thought it was.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at [email protected]

How much do I make compared with other doctors?

I see questions like that on surveys I get, asking me to fill something out on the Internet, then I’ll get back a list of how well other docs in my field/city/state/blood type are doing.

Nah. I’ll pass.

Realistically, why? So I can feel I’m superior or inferior to others? Isn’t keeping up with the Joneses the purpose of the doctors’ parking lot at the hospital? (Actually, the number of pricey cars there has dropped off over time).

I really don’t want to know how much others make. It’s probably more than what I make, but that’s the trade-off I accepted when I went with a small solo practice instead of a large group 20 years ago.

We become so obsessed with the question of “how much money should I be making?” and comparing it with the salaries of others that we lose track of the real question: “How much money do I need?”

That should be the real number to look at. How much money do I really need to pay for a comfortable home, support my family, pay for my kids’ education, fund my retirement?

Enough should be as good as a feast.

Yet, even when content we get caught in the trap of comparing ourselves with others. This is human nature. We’re programmed to be competitive to survive. Whether that means anything when we don’t have to be hunters and gatherers is irrelevant. It is who we are.

But we’re also intelligent enough to realize that. I for one, don’t want to know, or care, how much money the neurologist down the street is earning. All that matters to me is how much I am earning, and if it supports what I need it to.

To quote Sheryl Crow, “it’s not having what you want, it’s wanting what you’ve got.”

So I’ll skip the comparisons and focus on the only people that really matter to me.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

How much do I make compared with other doctors?

I see questions like that on surveys I get, asking me to fill something out on the Internet, then I’ll get back a list of how well other docs in my field/city/state/blood type are doing.

Nah. I’ll pass.

Realistically, why? So I can feel I’m superior or inferior to others? Isn’t keeping up with the Joneses the purpose of the doctors’ parking lot at the hospital? (Actually, the number of pricey cars there has dropped off over time).

I really don’t want to know how much others make. It’s probably more than what I make, but that’s the trade-off I accepted when I went with a small solo practice instead of a large group 20 years ago.

We become so obsessed with the question of “how much money should I be making?” and comparing it with the salaries of others that we lose track of the real question: “How much money do I need?”

That should be the real number to look at. How much money do I really need to pay for a comfortable home, support my family, pay for my kids’ education, fund my retirement?

Enough should be as good as a feast.

Yet, even when content we get caught in the trap of comparing ourselves with others. This is human nature. We’re programmed to be competitive to survive. Whether that means anything when we don’t have to be hunters and gatherers is irrelevant. It is who we are.

But we’re also intelligent enough to realize that. I for one, don’t want to know, or care, how much money the neurologist down the street is earning. All that matters to me is how much I am earning, and if it supports what I need it to.

To quote Sheryl Crow, “it’s not having what you want, it’s wanting what you’ve got.”

So I’ll skip the comparisons and focus on the only people that really matter to me.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

How much do I make compared with other doctors?

I see questions like that on surveys I get, asking me to fill something out on the Internet, then I’ll get back a list of how well other docs in my field/city/state/blood type are doing.

Nah. I’ll pass.

Realistically, why? So I can feel I’m superior or inferior to others? Isn’t keeping up with the Joneses the purpose of the doctors’ parking lot at the hospital? (Actually, the number of pricey cars there has dropped off over time).

I really don’t want to know how much others make. It’s probably more than what I make, but that’s the trade-off I accepted when I went with a small solo practice instead of a large group 20 years ago.

We become so obsessed with the question of “how much money should I be making?” and comparing it with the salaries of others that we lose track of the real question: “How much money do I need?”

That should be the real number to look at. How much money do I really need to pay for a comfortable home, support my family, pay for my kids’ education, fund my retirement?

Enough should be as good as a feast.

Yet, even when content we get caught in the trap of comparing ourselves with others. This is human nature. We’re programmed to be competitive to survive. Whether that means anything when we don’t have to be hunters and gatherers is irrelevant. It is who we are.

But we’re also intelligent enough to realize that. I for one, don’t want to know, or care, how much money the neurologist down the street is earning. All that matters to me is how much I am earning, and if it supports what I need it to.

To quote Sheryl Crow, “it’s not having what you want, it’s wanting what you’ve got.”

So I’ll skip the comparisons and focus on the only people that really matter to me.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Amyloidosis consists of approximately 30 protein-folding disorders sharing the common feature of abnormal extracellular amyloid deposition. In each condition, a specific soluble precursor protein aggregates to form the insoluble fibrils of amyloid, characterized by the beta-pleated sheet structure.¹ Amyloidosis occurs as either a systemic or localized process. Insulin-derived (AIns) amyloidosis, a localized process occurring at insulin injection sites, was first reported in 1983.² There were fewer than 20 reported cases until 2014, when 57 additional cases were reported by just 2 institutions,^3,4 indicating that AIns amyloidosis may be more common than previously thought.^3,5

Despite the increasing prevalence of diabetes mellitus and insulin use, there is a paucity of published cases of AIns amyloidosis. The lack of awareness of this condition among both dermatologists and general practitioners may be in part due to its variable clinical manifestations. We describe 2 patients with unique presentations of localized amyloidosis at repeated insulin injection sites.

Case Reports

Patient 1
A 39-year-old man with a history of type 1 diabetes mellitus presented with 4 asymptomatic nodules on the lateral thighs in areas of previous insulin injection. He first noticed the lesions 9 months prior to presentation and subsequently switched the injection site to the abdomen without development of new nodules. Despite being compliant with his insulin regimen, he had a long history of irregular glucose control, including frequent hypoglycemic episodes. The patient was using regular and neutral protamine hagedorn insulin.

On physical examination, 2 soft, nontender, exophytic nodules were noted on each upper thigh with surrounding hyperpigmented and hyperkeratotic collarettes (Figure 1). The nodules ranged in size from 2 to 3.5 cm in diameter.

Patient 2
A 53-year-old woman with a history of type 2 diabetes mellitus presented with painful subcutaneous nodules on the lower abdomen at sites of previous insulin injections. The nodules developed approximately 1 month after she started treatment with neutral protamine hagedorn insulin and had been slowly enlarging over the past year. She tried switching injection sites after noticing the lesions, but the nodules persisted. The patient had a long history of poor glucose control with chronically elevated glycohemoglobin and blood glucose levels.

On physical examination, 2 hyperpigmented, exophytic, smooth nodules were noted on the right and left lower abdomen, ranging in size from 2.5 to 5.5 cm in diameter (Figure 4).

Comment

Insulin is the suspected precursor protein in AIns amyloidosis, but the exact pathogenesis is unknown. The protein that is derived from insulin in these tumors is now identified as AIns amyloidosis.^5,6 It is hypothesized that insulin accumulates locally and is converted to amyloid by an unknown mechanism.⁷ Other potential contributory factors include chronic inflammation and foreign body reactions developing around amyloid deposits, as well as repeated trauma from injections into a single site.^4,5 It appears that lesions may derive from a wide range of insulin types and occur after variable time periods.

A majority of cases of iatrogenic amyloid have been described as single, firm, subcutaneous masses at an injection site that commonly are misdiagnosed as lipomas or lipohypertrophy.^7-11 To our knowledge, none of the reported cases resembled the multiple, discrete, exophytic nodules seen in our patients.^3,4 The surrounding hyperkeratosis noted in patient 1 is another uncommon feature of AIns amyloidosis (Figures 1 and 2). Only 3 AIns amyloidosis cases described lesions with acanthosis nigricans–like changes, only 1 of which provided a clinical image.^6,7,12The mechanism for the acanthosis nigricans–like changes may have been due to the high levels of insulin at the injection site. It has been suggested that the activation of insulinlike growth factor receptor by insulin leads to the proliferation of keratinocytes and fibroblasts.⁶ Histologic examination of AIns amyloidosis lesions generally demonstrates deposition of homogenous eosinophilic material consistent with amyloid, as well as positive Congo red staining with green birefringence by polarization. Immunohistologic staining with insulin antibody with or without proteomic analysis of the amyloid deposits can confirm the diagnosis. In both of our patients’ specimens, liquid chromatography–tandem mass spectrometry was performed for proteomic analysis, and results were consistent with AIns amyloidosis.

Reports in the literature have suggested that the deposition of amyloid at insulin injection sites has the potential to interfere with insulin absorption, leading to poor glucose control.^4,11,13 Hence, injection site rotation is a crucial aspect of treatment and prevention of AIns amyloidosis. In their study of 4 patients, Nagase et al⁴ compared serum insulin levels after insulin injection into amyloid nodules vs insulin levels after injection into normal skin. Insulin absorption at the amyloid sites was 34% of that at normal sites. Given these results, patients should be instructed to inject away from the amyloid deposit once it is identified.⁶ Glucose levels should be monitored closely when patients first inject away from the amyloid mass, as injection of the same dosage to an area of normal skin can lead to increased insulin absorption and hypoglycemia.^4,6 It is possible that the frequent hypoglycemic episodes noted in patient 1 were due to increased insulin sensitivity after switching to injection sites away from amyloid lesions.

Conclusion

Our patients demonstrate unique presentations of localized cutaneous amyloidosis at repeated insulin injection sites. We report these cases to complement the current data of iatrogenic amyloidosis and provide insight into this likely underreported phenomenon.

Amyloidosis consists of approximately 30 protein-folding disorders sharing the common feature of abnormal extracellular amyloid deposition. In each condition, a specific soluble precursor protein aggregates to form the insoluble fibrils of amyloid, characterized by the beta-pleated sheet structure.¹ Amyloidosis occurs as either a systemic or localized process. Insulin-derived (AIns) amyloidosis, a localized process occurring at insulin injection sites, was first reported in 1983.² There were fewer than 20 reported cases until 2014, when 57 additional cases were reported by just 2 institutions,^3,4 indicating that AIns amyloidosis may be more common than previously thought.^3,5

Despite the increasing prevalence of diabetes mellitus and insulin use, there is a paucity of published cases of AIns amyloidosis. The lack of awareness of this condition among both dermatologists and general practitioners may be in part due to its variable clinical manifestations. We describe 2 patients with unique presentations of localized amyloidosis at repeated insulin injection sites.

Case Reports

Patient 1
A 39-year-old man with a history of type 1 diabetes mellitus presented with 4 asymptomatic nodules on the lateral thighs in areas of previous insulin injection. He first noticed the lesions 9 months prior to presentation and subsequently switched the injection site to the abdomen without development of new nodules. Despite being compliant with his insulin regimen, he had a long history of irregular glucose control, including frequent hypoglycemic episodes. The patient was using regular and neutral protamine hagedorn insulin.

On physical examination, 2 soft, nontender, exophytic nodules were noted on each upper thigh with surrounding hyperpigmented and hyperkeratotic collarettes (Figure 1). The nodules ranged in size from 2 to 3.5 cm in diameter.

Patient 2
A 53-year-old woman with a history of type 2 diabetes mellitus presented with painful subcutaneous nodules on the lower abdomen at sites of previous insulin injections. The nodules developed approximately 1 month after she started treatment with neutral protamine hagedorn insulin and had been slowly enlarging over the past year. She tried switching injection sites after noticing the lesions, but the nodules persisted. The patient had a long history of poor glucose control with chronically elevated glycohemoglobin and blood glucose levels.

On physical examination, 2 hyperpigmented, exophytic, smooth nodules were noted on the right and left lower abdomen, ranging in size from 2.5 to 5.5 cm in diameter (Figure 4).

Comment

Insulin is the suspected precursor protein in AIns amyloidosis, but the exact pathogenesis is unknown. The protein that is derived from insulin in these tumors is now identified as AIns amyloidosis.^5,6 It is hypothesized that insulin accumulates locally and is converted to amyloid by an unknown mechanism.⁷ Other potential contributory factors include chronic inflammation and foreign body reactions developing around amyloid deposits, as well as repeated trauma from injections into a single site.^4,5 It appears that lesions may derive from a wide range of insulin types and occur after variable time periods.

A majority of cases of iatrogenic amyloid have been described as single, firm, subcutaneous masses at an injection site that commonly are misdiagnosed as lipomas or lipohypertrophy.^7-11 To our knowledge, none of the reported cases resembled the multiple, discrete, exophytic nodules seen in our patients.^3,4 The surrounding hyperkeratosis noted in patient 1 is another uncommon feature of AIns amyloidosis (Figures 1 and 2). Only 3 AIns amyloidosis cases described lesions with acanthosis nigricans–like changes, only 1 of which provided a clinical image.^6,7,12The mechanism for the acanthosis nigricans–like changes may have been due to the high levels of insulin at the injection site. It has been suggested that the activation of insulinlike growth factor receptor by insulin leads to the proliferation of keratinocytes and fibroblasts.⁶ Histologic examination of AIns amyloidosis lesions generally demonstrates deposition of homogenous eosinophilic material consistent with amyloid, as well as positive Congo red staining with green birefringence by polarization. Immunohistologic staining with insulin antibody with or without proteomic analysis of the amyloid deposits can confirm the diagnosis. In both of our patients’ specimens, liquid chromatography–tandem mass spectrometry was performed for proteomic analysis, and results were consistent with AIns amyloidosis.

Reports in the literature have suggested that the deposition of amyloid at insulin injection sites has the potential to interfere with insulin absorption, leading to poor glucose control.^4,11,13 Hence, injection site rotation is a crucial aspect of treatment and prevention of AIns amyloidosis. In their study of 4 patients, Nagase et al⁴ compared serum insulin levels after insulin injection into amyloid nodules vs insulin levels after injection into normal skin. Insulin absorption at the amyloid sites was 34% of that at normal sites. Given these results, patients should be instructed to inject away from the amyloid deposit once it is identified.⁶ Glucose levels should be monitored closely when patients first inject away from the amyloid mass, as injection of the same dosage to an area of normal skin can lead to increased insulin absorption and hypoglycemia.^4,6 It is possible that the frequent hypoglycemic episodes noted in patient 1 were due to increased insulin sensitivity after switching to injection sites away from amyloid lesions.

Conclusion

Our patients demonstrate unique presentations of localized cutaneous amyloidosis at repeated insulin injection sites. We report these cases to complement the current data of iatrogenic amyloidosis and provide insight into this likely underreported phenomenon.

Amyloidosis consists of approximately 30 protein-folding disorders sharing the common feature of abnormal extracellular amyloid deposition. In each condition, a specific soluble precursor protein aggregates to form the insoluble fibrils of amyloid, characterized by the beta-pleated sheet structure.¹ Amyloidosis occurs as either a systemic or localized process. Insulin-derived (AIns) amyloidosis, a localized process occurring at insulin injection sites, was first reported in 1983.² There were fewer than 20 reported cases until 2014, when 57 additional cases were reported by just 2 institutions,^3,4 indicating that AIns amyloidosis may be more common than previously thought.^3,5

Despite the increasing prevalence of diabetes mellitus and insulin use, there is a paucity of published cases of AIns amyloidosis. The lack of awareness of this condition among both dermatologists and general practitioners may be in part due to its variable clinical manifestations. We describe 2 patients with unique presentations of localized amyloidosis at repeated insulin injection sites.

Case Reports

Patient 1
A 39-year-old man with a history of type 1 diabetes mellitus presented with 4 asymptomatic nodules on the lateral thighs in areas of previous insulin injection. He first noticed the lesions 9 months prior to presentation and subsequently switched the injection site to the abdomen without development of new nodules. Despite being compliant with his insulin regimen, he had a long history of irregular glucose control, including frequent hypoglycemic episodes. The patient was using regular and neutral protamine hagedorn insulin.

On physical examination, 2 soft, nontender, exophytic nodules were noted on each upper thigh with surrounding hyperpigmented and hyperkeratotic collarettes (Figure 1). The nodules ranged in size from 2 to 3.5 cm in diameter.

Patient 2
A 53-year-old woman with a history of type 2 diabetes mellitus presented with painful subcutaneous nodules on the lower abdomen at sites of previous insulin injections. The nodules developed approximately 1 month after she started treatment with neutral protamine hagedorn insulin and had been slowly enlarging over the past year. She tried switching injection sites after noticing the lesions, but the nodules persisted. The patient had a long history of poor glucose control with chronically elevated glycohemoglobin and blood glucose levels.

On physical examination, 2 hyperpigmented, exophytic, smooth nodules were noted on the right and left lower abdomen, ranging in size from 2.5 to 5.5 cm in diameter (Figure 4).

Comment

Insulin is the suspected precursor protein in AIns amyloidosis, but the exact pathogenesis is unknown. The protein that is derived from insulin in these tumors is now identified as AIns amyloidosis.^5,6 It is hypothesized that insulin accumulates locally and is converted to amyloid by an unknown mechanism.⁷ Other potential contributory factors include chronic inflammation and foreign body reactions developing around amyloid deposits, as well as repeated trauma from injections into a single site.^4,5 It appears that lesions may derive from a wide range of insulin types and occur after variable time periods.

A majority of cases of iatrogenic amyloid have been described as single, firm, subcutaneous masses at an injection site that commonly are misdiagnosed as lipomas or lipohypertrophy.^7-11 To our knowledge, none of the reported cases resembled the multiple, discrete, exophytic nodules seen in our patients.^3,4 The surrounding hyperkeratosis noted in patient 1 is another uncommon feature of AIns amyloidosis (Figures 1 and 2). Only 3 AIns amyloidosis cases described lesions with acanthosis nigricans–like changes, only 1 of which provided a clinical image.^6,7,12The mechanism for the acanthosis nigricans–like changes may have been due to the high levels of insulin at the injection site. It has been suggested that the activation of insulinlike growth factor receptor by insulin leads to the proliferation of keratinocytes and fibroblasts.⁶ Histologic examination of AIns amyloidosis lesions generally demonstrates deposition of homogenous eosinophilic material consistent with amyloid, as well as positive Congo red staining with green birefringence by polarization. Immunohistologic staining with insulin antibody with or without proteomic analysis of the amyloid deposits can confirm the diagnosis. In both of our patients’ specimens, liquid chromatography–tandem mass spectrometry was performed for proteomic analysis, and results were consistent with AIns amyloidosis.

Reports in the literature have suggested that the deposition of amyloid at insulin injection sites has the potential to interfere with insulin absorption, leading to poor glucose control.^4,11,13 Hence, injection site rotation is a crucial aspect of treatment and prevention of AIns amyloidosis. In their study of 4 patients, Nagase et al⁴ compared serum insulin levels after insulin injection into amyloid nodules vs insulin levels after injection into normal skin. Insulin absorption at the amyloid sites was 34% of that at normal sites. Given these results, patients should be instructed to inject away from the amyloid deposit once it is identified.⁶ Glucose levels should be monitored closely when patients first inject away from the amyloid mass, as injection of the same dosage to an area of normal skin can lead to increased insulin absorption and hypoglycemia.^4,6 It is possible that the frequent hypoglycemic episodes noted in patient 1 were due to increased insulin sensitivity after switching to injection sites away from amyloid lesions.

Conclusion

Our patients demonstrate unique presentations of localized cutaneous amyloidosis at repeated insulin injection sites. We report these cases to complement the current data of iatrogenic amyloidosis and provide insight into this likely underreported phenomenon.

For patients with intermediate- or high-risk ductal carcinoma in situ (DCIS) treated with conservative surgery and whole breast irradiation (WBI), adding a boost dose to the tumor bed significantly reduced the risk of recurrence, regardless of WBI fractionation, in the BIG-3-07/TROG 07.01 trial.

Giving a tumor bed boost (TBB) reduced the risk of local recurrence and overall disease recurrence, but there were no significant differences in recurrence rates between conventional WBI and hypofractionated WBI.

Boon Hui Chua, MD, of the University of New South Wales, Sydney, presented these results at the 2020 San Antonio Breast Cancer Symposium.

Dr. Chua and colleagues studied 1,608 women with DCIS resected by conservative surgery. Patients were either younger than 50 years or age 50 and older with at least one of the following risk factors: symptomatic presentation, palpable tumor, multifocal disease, tumor size 1.5 cm or larger, intermediate or high nuclear grade, central necrosis, comedo histology, and/or surgical margins less than 10 mm.

The patients were randomized to treatment in three categories. In randomization A (n = 503), patients were randomized to one of the following treatments:

• WBI at 50 Gy in 25 fractions
• WBI at 42.5 Gy in 16 fractions
• WBI at 50 Gy in 25 fractions plus TBB at 16 Gy in 8 fractions
• WBI at 42.5 Gy in 16 fractions plus TBB at 16 Gy in 8 fractions.

In randomization B (n = 581), patients received WBI at 50 Gy in 25 fractions, with or without TBB at 16 Gy in 8 fractions. In randomization C (n = 524), patients received WBI at 42.5 Gy in 16 fractions, with or without TBB at 16 Gy in 8 fractions.

All patients underwent CT-based radiation planning. WBI was delivered with tangential MV photon beams, and TBB was performed with CT contouring of protocol-defined tumor bed target volumes, with electron or photon energy. The median follow-up was 6.6 years.
 

Giving a boost to better outcomes

The 5-year rate of freedom from local recurrence was 97% for patients who received TBB and 93% for patients who did not (hazard ratio, 0.47; P < .001). The benefit of TBB was consistent across subgroups.

There were no significant differences in 5-year rates of freedom from local recurrence by WBI fractionation, either in randomization A (P = .837) or among all randomized patients (P = .887).

The tests for interactions between TBB and WBI fractionation on local recurrence were not significant in randomization A (P = .89) or in all randomized patients (P = .89).

The risk of overall disease recurrence was lower among patients who had received TBB, with an HR of 0.63 (P = .004). The 5-year rate of freedom from disease recurrence was 97% with TBB and 91% with no boost (P = .002).

There were no significant differences in freedom from disease recurrence rates by WBI fractionation either in randomization A (P = .443) or among all randomized patients (P = .605).

Acute radiation dermatitis occurred in significantly more patients who received TBB (P = .006), as did late breast pain (P = .003), induration or fibrosis (P < .0001), and telangiectasia (P = .02). There were no significant differences by boost status for acute or late fatigue, pneumonitis, cardiac complications, or second malignancies.
 

Reduce the boost dose?

A radiation oncologist who was not involved in this study said that, while the results confirm a benefit of boost dose for patients with non–low-risk DCIS, the doses used in the BIG-3-07 study may be higher than needed to achieve a protective effect.

“Here in America, we usually give 10 Gy in five fractions, and, in many countries, actually, it’s 10 Gy in five fractions, although a few European centers give 16 Gy in eight fractions,” said Alphose Taghian, MD, of Massachusetts General Hospital in Boston.

“I personally only give 10 Gy in five fractions. I am not under the impression that 16 Gy in eight fractions will give better results. The local failure rate is so low, it’s likely that 10 Gy will do the job,” Dr. Taghian said in an interview.

Dr. Taghian noted that raising the dose to 16 Gy increases the risk of fibrosis, as seen in the BIG-3-07 trial.

Nonetheless, the trial demonstrates the benefit of radiation boost dose in patients with high-risk DCIS, he said, adding that the local recurrence-free benefit curves may separate further with longer follow-up.

The study was sponsored by the Trans Tasman Radiation Oncology Group. Dr. Chua and Dr. Taghian reported no conflicts of interest.

For patients with intermediate- or high-risk ductal carcinoma in situ (DCIS) treated with conservative surgery and whole breast irradiation (WBI), adding a boost dose to the tumor bed significantly reduced the risk of recurrence, regardless of WBI fractionation, in the BIG-3-07/TROG 07.01 trial.

Giving a tumor bed boost (TBB) reduced the risk of local recurrence and overall disease recurrence, but there were no significant differences in recurrence rates between conventional WBI and hypofractionated WBI.

Boon Hui Chua, MD, of the University of New South Wales, Sydney, presented these results at the 2020 San Antonio Breast Cancer Symposium.

Dr. Chua and colleagues studied 1,608 women with DCIS resected by conservative surgery. Patients were either younger than 50 years or age 50 and older with at least one of the following risk factors: symptomatic presentation, palpable tumor, multifocal disease, tumor size 1.5 cm or larger, intermediate or high nuclear grade, central necrosis, comedo histology, and/or surgical margins less than 10 mm.

The patients were randomized to treatment in three categories. In randomization A (n = 503), patients were randomized to one of the following treatments:

• WBI at 50 Gy in 25 fractions
• WBI at 42.5 Gy in 16 fractions
• WBI at 50 Gy in 25 fractions plus TBB at 16 Gy in 8 fractions
• WBI at 42.5 Gy in 16 fractions plus TBB at 16 Gy in 8 fractions.

In randomization B (n = 581), patients received WBI at 50 Gy in 25 fractions, with or without TBB at 16 Gy in 8 fractions. In randomization C (n = 524), patients received WBI at 42.5 Gy in 16 fractions, with or without TBB at 16 Gy in 8 fractions.

All patients underwent CT-based radiation planning. WBI was delivered with tangential MV photon beams, and TBB was performed with CT contouring of protocol-defined tumor bed target volumes, with electron or photon energy. The median follow-up was 6.6 years.
 

Giving a boost to better outcomes

The 5-year rate of freedom from local recurrence was 97% for patients who received TBB and 93% for patients who did not (hazard ratio, 0.47; P < .001). The benefit of TBB was consistent across subgroups.

There were no significant differences in 5-year rates of freedom from local recurrence by WBI fractionation, either in randomization A (P = .837) or among all randomized patients (P = .887).

The tests for interactions between TBB and WBI fractionation on local recurrence were not significant in randomization A (P = .89) or in all randomized patients (P = .89).

The risk of overall disease recurrence was lower among patients who had received TBB, with an HR of 0.63 (P = .004). The 5-year rate of freedom from disease recurrence was 97% with TBB and 91% with no boost (P = .002).

There were no significant differences in freedom from disease recurrence rates by WBI fractionation either in randomization A (P = .443) or among all randomized patients (P = .605).

Acute radiation dermatitis occurred in significantly more patients who received TBB (P = .006), as did late breast pain (P = .003), induration or fibrosis (P < .0001), and telangiectasia (P = .02). There were no significant differences by boost status for acute or late fatigue, pneumonitis, cardiac complications, or second malignancies.
 

Reduce the boost dose?

A radiation oncologist who was not involved in this study said that, while the results confirm a benefit of boost dose for patients with non–low-risk DCIS, the doses used in the BIG-3-07 study may be higher than needed to achieve a protective effect.

“Here in America, we usually give 10 Gy in five fractions, and, in many countries, actually, it’s 10 Gy in five fractions, although a few European centers give 16 Gy in eight fractions,” said Alphose Taghian, MD, of Massachusetts General Hospital in Boston.

“I personally only give 10 Gy in five fractions. I am not under the impression that 16 Gy in eight fractions will give better results. The local failure rate is so low, it’s likely that 10 Gy will do the job,” Dr. Taghian said in an interview.

Dr. Taghian noted that raising the dose to 16 Gy increases the risk of fibrosis, as seen in the BIG-3-07 trial.

Nonetheless, the trial demonstrates the benefit of radiation boost dose in patients with high-risk DCIS, he said, adding that the local recurrence-free benefit curves may separate further with longer follow-up.

The study was sponsored by the Trans Tasman Radiation Oncology Group. Dr. Chua and Dr. Taghian reported no conflicts of interest.

For patients with intermediate- or high-risk ductal carcinoma in situ (DCIS) treated with conservative surgery and whole breast irradiation (WBI), adding a boost dose to the tumor bed significantly reduced the risk of recurrence, regardless of WBI fractionation, in the BIG-3-07/TROG 07.01 trial.

Giving a tumor bed boost (TBB) reduced the risk of local recurrence and overall disease recurrence, but there were no significant differences in recurrence rates between conventional WBI and hypofractionated WBI.

Boon Hui Chua, MD, of the University of New South Wales, Sydney, presented these results at the 2020 San Antonio Breast Cancer Symposium.

Dr. Chua and colleagues studied 1,608 women with DCIS resected by conservative surgery. Patients were either younger than 50 years or age 50 and older with at least one of the following risk factors: symptomatic presentation, palpable tumor, multifocal disease, tumor size 1.5 cm or larger, intermediate or high nuclear grade, central necrosis, comedo histology, and/or surgical margins less than 10 mm.

The patients were randomized to treatment in three categories. In randomization A (n = 503), patients were randomized to one of the following treatments:

• WBI at 50 Gy in 25 fractions
• WBI at 42.5 Gy in 16 fractions
• WBI at 50 Gy in 25 fractions plus TBB at 16 Gy in 8 fractions
• WBI at 42.5 Gy in 16 fractions plus TBB at 16 Gy in 8 fractions.

In randomization B (n = 581), patients received WBI at 50 Gy in 25 fractions, with or without TBB at 16 Gy in 8 fractions. In randomization C (n = 524), patients received WBI at 42.5 Gy in 16 fractions, with or without TBB at 16 Gy in 8 fractions.

All patients underwent CT-based radiation planning. WBI was delivered with tangential MV photon beams, and TBB was performed with CT contouring of protocol-defined tumor bed target volumes, with electron or photon energy. The median follow-up was 6.6 years.
 

Giving a boost to better outcomes

The 5-year rate of freedom from local recurrence was 97% for patients who received TBB and 93% for patients who did not (hazard ratio, 0.47; P < .001). The benefit of TBB was consistent across subgroups.

There were no significant differences in 5-year rates of freedom from local recurrence by WBI fractionation, either in randomization A (P = .837) or among all randomized patients (P = .887).

The tests for interactions between TBB and WBI fractionation on local recurrence were not significant in randomization A (P = .89) or in all randomized patients (P = .89).

The risk of overall disease recurrence was lower among patients who had received TBB, with an HR of 0.63 (P = .004). The 5-year rate of freedom from disease recurrence was 97% with TBB and 91% with no boost (P = .002).

There were no significant differences in freedom from disease recurrence rates by WBI fractionation either in randomization A (P = .443) or among all randomized patients (P = .605).

Acute radiation dermatitis occurred in significantly more patients who received TBB (P = .006), as did late breast pain (P = .003), induration or fibrosis (P < .0001), and telangiectasia (P = .02). There were no significant differences by boost status for acute or late fatigue, pneumonitis, cardiac complications, or second malignancies.
 

Reduce the boost dose?

A radiation oncologist who was not involved in this study said that, while the results confirm a benefit of boost dose for patients with non–low-risk DCIS, the doses used in the BIG-3-07 study may be higher than needed to achieve a protective effect.

“Here in America, we usually give 10 Gy in five fractions, and, in many countries, actually, it’s 10 Gy in five fractions, although a few European centers give 16 Gy in eight fractions,” said Alphose Taghian, MD, of Massachusetts General Hospital in Boston.

“I personally only give 10 Gy in five fractions. I am not under the impression that 16 Gy in eight fractions will give better results. The local failure rate is so low, it’s likely that 10 Gy will do the job,” Dr. Taghian said in an interview.

Dr. Taghian noted that raising the dose to 16 Gy increases the risk of fibrosis, as seen in the BIG-3-07 trial.

Nonetheless, the trial demonstrates the benefit of radiation boost dose in patients with high-risk DCIS, he said, adding that the local recurrence-free benefit curves may separate further with longer follow-up.

The study was sponsored by the Trans Tasman Radiation Oncology Group. Dr. Chua and Dr. Taghian reported no conflicts of interest.