Febrile neutropenia (FN) frequently occurs in patients receiving chemotherapy, with the greatest risk of complications occurring in those who experience profound and prolonged neutropenia. Although granulocyte colony-stimulating factor (G-CSF) prophylaxis has been shown to reduce the risk and duration of chemotherapy-induced neutropenia and FN, there is no well-established optimal regimen.¹ The 2022 National Comprehensive Cancer Network guidelines for hematopoietic growth factors recommend prophylaxis with G-CSF in at-risk patients receiving chemotherapy, specifically in chemotherapy regimens considered high risk for FN (incidence > 20%) or intermediate risk for FN (incidence 10%-20%) with additional patient risk factors.² The incidence of developing FN with at least 1 chemotherapy cycle is estimated at 10% to 50% of patients with solid tumors and > 80% of patients with hematologic malignancies.³ The rate of major complications (eg, hypotension, acute renal, respiratory, or heart failure) in the context of FN is 25% to 30%, and mortality is reported up to 11% in this population.⁴

Because of the significant consequences of neutropenia and FN, prevention is imperative due to the increase in morbidity and mortality, including chemotherapy delays, increased hospitalizations, chemotherapy dose reductions, and discontinuations that cause delays in care.⁵ In patients with curative malignancies, these consequences can negatively impact treatment efficacy and overall survival. Additionally, infections occur in 20% to 30% of patients with febrile episodes. Although fever is often the only clinical sign or symptom of infection, patients who are profoundly neutropenic may present with suspected infection and be afebrile or hypothermic.³

For filgrastim, the National Comprehensive Cancer Network guidelines do not specify the total days of required injections but state that a daily dose should be given until the postnadir absolute neutrophil count (ANC) recovers to normal or near normal levels by laboratory standards.² It is uncommon in clinical practice to track postnadir ANCs due to frequent laboratory monitoring. Clinical trial data suggest an average duration of 11 days of daily filgrastim injections for ANC recovery; however, real-world data exist supporting a range from 4 to 10 days with a median of 7 injections per cycle for prevention of neutropenia or FN.^6,7

At the South Texas Veterans Health Care System in San Antonio, daily filgrastim injections are preferred due to cost; patients typically receive a 7-day course for primary prophylaxis for FN. In our study, we aimed to determine the outcomes in patients receiving daily filgrastim injections with a curative cancer diagnosis and a chemotherapy regimen with either high risk for FN, or a chemotherapy regimen with an intermediate risk for FN and additional patient risk factors. Before the initiation of data collection, this study was reviewed and determined to be exempt by the University of Texas Health Science Center at San Antonio Institutional Review Board.

METHODS

Electronic health record reviews at the South Texas Veterans Health Care System were performed to identify patients who received filgrastim primary prophylaxis (defined as filgrastim, tbo-filgrastim, or filgrastim-sndz) for a curative cancer diagnosis. Primary prophylaxis refers to the administration of G-CSF in the first cycle of chemotherapy before the onset of neutropenia. Patients received filgrastim prophylaxis if they were undergoing treatment with a chemotherapy regimen with either high risk for FN or a chemotherapy regimen with an intermediate risk for FN and additional patient risk factors. Risk factors for patients included prior chemotherapy or radiation therapy; persistent neutropenia; bone marrow involvement by tumor; recent surgery and/or open wounds; liver dysfunction (defined as total bilirubin > 2 mg/dL); renal dysfunction (defined as creatinine clearance < 50 mL/min); and those aged > 65 years receiving full chemotherapy dose intensity. Neutropenia is defined as a decrease in ANC < 1000 neutrophils/μL, whereas FN is defined as a single temperature of > 38.3 °C or > 38.0 °C for longer than 1 hour with < 500 neutrophils/μL or < 1000 neutrophils/μL predicted to decline to < 500 neutrophils/μL over the next 48 hours. All patients had their filgrastim dispensed for home administration during their chemotherapy appointment.

Patients were included if they received filgrastim for primary prophylaxis of FN with a curative cancer diagnosis. Patients receiving salvage chemotherapy for hematologic malignancies with intent to proceed to curative transplant were also included. Bone marrow involvement of the tumor is a FN risk factor. Only patients with hematologic malignancies and bone marrow involvement were included. Patients wereexcluded if they received filgrastim for secondary prophylaxis of neutropenia or FN, a noncurative cancer diagnosis, stem cell transplant mobilization and engraftment, or nononcologic neutropenia.

The primary outcome for this study was the incidence of neutropenia or FN leading to treatment delays despite the use of primary prophylaxis with filgrastim. A dose delay was defined as a delay of planned chemotherapy by ≥ 3 days. Secondary outcomes included chemotherapy dose decreases or discontinuations, hospitalizations, days of hospitalization, infections, extended duration of filgrastim, and transitions to pegfilgrastim due to neutropenia or FN. Documented infections were defined in patients with a positive culture, laboratory testing, or imaging consistent with infection. Extended durations of filgrastim or transitions to pegfilgrastim were patient specific and upon clinician discretion.

Descriptive statistics were used to summarize the study population and their health outcomes. Fisher exact test was used to compare FN incidence for high- and intermediate-risk FN groups.

RESULTS

Between September 1, 2015, and September 24, 2020, 381 patients received filgrastim. Of these patients, 59 met the inclusion criteria. Patients receiving filgrastim were excluded due to stem cell transplant mobilization/engraftment (n = 145), a noncurative cancer diagnosis (n = 134), use as a secondary prophylaxis (n = 33), and nononcologic neutropenia (n = 8). Additionally, 2 patients initially received pegfilgrastim and were not included in this data set.

The median (IQR) age was 64 (55-70) years and 42 patients (71%) were male (Table 1).

Ten patients (17%) experienced dose delays despite filgrastim use (Table 2).

DISCUSSION

Real-world data are limited regarding G-CSF practice patterns; however, available data demonstrate patients may receive suboptimal treatment courses of filgrastim leading to increased complications associated with neutropenia and FN, such as dose delays and hospitalizations.^8,9 At the South Texas Veterans Health Care System, 48 patients (81%) received a filgrastim course of ≥ 7 days as an initial course for primary prophylaxis. Multivariate analyses performed by Weycker and colleagues described a decreased risk of hospitalization for neutropenia or FN with each additional day of filgrastim prophylaxis; however, such analysis could not be performed in our data set due to the small sample size.⁸ In this review, 10 patients (17%) experienced treatment delays due to neutropenia or FN, mirroring previously published data. The hospitalization rate of 25% is higher than the published incidence of 5.2% of cancer-related hospitalizations among adults.^7,10 This difference may be explained by a difference in health care access for the veteran population.

As an alternative to daily filgrastim injections, the National Comprehensive Cancer Network also recommends a single dose of pegfilgrastim for primary prevention of FN. Efficacy benefits of pegfilgrastim use include increased patient adherence due to a single injection, a reduction in FN incidence and FN-related hospitalizations, and improved time to ANC recovery compared with filgrastim.¹¹ There are reports suggesting pegfilgrastim significantly reduces neutropenia and FN incidence to a greater extent compared with daily filgrastim injections.⁶ In patients with breast cancer receiving dose-dense adjuvant chemotherapy, there are data demonstrating that patients who received filgrastim were more likely to experience severe neutropenia, dose reductions, and treatment delays leading to lower dose density compared with pegfilgrastim.¹² Of the 19 patients with breast cancer included in our population, 26% experienced one of the previously described outcomes leading to either extensions of daily filgrastim injections or transitions to pegfilgrastim to successfully maintain dose density. In patients with acute myeloid leukemia receiving consolidation chemotherapy, filgrastim was found to be associated with a statistically significant increased risk of hospitalizations compared with pegfilgrastim.¹³ The one patient with acute myeloid leukemia included in our study did not require additional hospitalizations for neutropenia or FN after transitioning to pegfilgrastim.

Given the cost advantage, the South Texas Veterans Health Care System continues to prefer daily filgrastim injections. A recent survey demonstrated that 73% of patients at 23 sites in the Veterans Health Administration used filgrastim rather than pegfilgrastim for cost savings, although it is recognized that daily filgrastim injections are less convenient for patients.¹⁴ This analysis did not review costs associated with hospitalization for FN or the appropriateness of G-CSF use. Cancer-related neutropenia accounts for 8.3% of all cancer-related hospitalization costs among adults; the average hospitalization costs nearly $25,000 per stay and about $2.3 billion among adult patients with cancer annually.^10,15

Limitations

This study has limitations that affected the applicability and interpretation of the results. This included the study design since it was a retrospective, single-center, descriptive cohort study. Patient adherence to daily filgrastim injections could not be assessed due to the retrospective nature of the study. The small sample size of 59 patients was prohibitive for utilization of additional analytical tools. Additionally, the predominately male veteran population may make applicability to non-VA populations restrictive.

CONCLUSIONS

Based on the incidence of primary and secondary outcomes associated with using daily filgrastim injections as primary prophylaxis in this study, additional measures such as tracking postnadir ANCs should be performed to ensure patients receive an appropriate number of filgrastim doses to prevent complications associated with neutropenia.

Acknowledgments

We thank Eric Dougherty, PharmD, for assistance in producing granulocyte colony-stimulating factor data.

Febrile neutropenia (FN) frequently occurs in patients receiving chemotherapy, with the greatest risk of complications occurring in those who experience profound and prolonged neutropenia. Although granulocyte colony-stimulating factor (G-CSF) prophylaxis has been shown to reduce the risk and duration of chemotherapy-induced neutropenia and FN, there is no well-established optimal regimen.¹ The 2022 National Comprehensive Cancer Network guidelines for hematopoietic growth factors recommend prophylaxis with G-CSF in at-risk patients receiving chemotherapy, specifically in chemotherapy regimens considered high risk for FN (incidence > 20%) or intermediate risk for FN (incidence 10%-20%) with additional patient risk factors.² The incidence of developing FN with at least 1 chemotherapy cycle is estimated at 10% to 50% of patients with solid tumors and > 80% of patients with hematologic malignancies.³ The rate of major complications (eg, hypotension, acute renal, respiratory, or heart failure) in the context of FN is 25% to 30%, and mortality is reported up to 11% in this population.⁴

Because of the significant consequences of neutropenia and FN, prevention is imperative due to the increase in morbidity and mortality, including chemotherapy delays, increased hospitalizations, chemotherapy dose reductions, and discontinuations that cause delays in care.⁵ In patients with curative malignancies, these consequences can negatively impact treatment efficacy and overall survival. Additionally, infections occur in 20% to 30% of patients with febrile episodes. Although fever is often the only clinical sign or symptom of infection, patients who are profoundly neutropenic may present with suspected infection and be afebrile or hypothermic.³

For filgrastim, the National Comprehensive Cancer Network guidelines do not specify the total days of required injections but state that a daily dose should be given until the postnadir absolute neutrophil count (ANC) recovers to normal or near normal levels by laboratory standards.² It is uncommon in clinical practice to track postnadir ANCs due to frequent laboratory monitoring. Clinical trial data suggest an average duration of 11 days of daily filgrastim injections for ANC recovery; however, real-world data exist supporting a range from 4 to 10 days with a median of 7 injections per cycle for prevention of neutropenia or FN.^6,7

At the South Texas Veterans Health Care System in San Antonio, daily filgrastim injections are preferred due to cost; patients typically receive a 7-day course for primary prophylaxis for FN. In our study, we aimed to determine the outcomes in patients receiving daily filgrastim injections with a curative cancer diagnosis and a chemotherapy regimen with either high risk for FN, or a chemotherapy regimen with an intermediate risk for FN and additional patient risk factors. Before the initiation of data collection, this study was reviewed and determined to be exempt by the University of Texas Health Science Center at San Antonio Institutional Review Board.

METHODS

Electronic health record reviews at the South Texas Veterans Health Care System were performed to identify patients who received filgrastim primary prophylaxis (defined as filgrastim, tbo-filgrastim, or filgrastim-sndz) for a curative cancer diagnosis. Primary prophylaxis refers to the administration of G-CSF in the first cycle of chemotherapy before the onset of neutropenia. Patients received filgrastim prophylaxis if they were undergoing treatment with a chemotherapy regimen with either high risk for FN or a chemotherapy regimen with an intermediate risk for FN and additional patient risk factors. Risk factors for patients included prior chemotherapy or radiation therapy; persistent neutropenia; bone marrow involvement by tumor; recent surgery and/or open wounds; liver dysfunction (defined as total bilirubin > 2 mg/dL); renal dysfunction (defined as creatinine clearance < 50 mL/min); and those aged > 65 years receiving full chemotherapy dose intensity. Neutropenia is defined as a decrease in ANC < 1000 neutrophils/μL, whereas FN is defined as a single temperature of > 38.3 °C or > 38.0 °C for longer than 1 hour with < 500 neutrophils/μL or < 1000 neutrophils/μL predicted to decline to < 500 neutrophils/μL over the next 48 hours. All patients had their filgrastim dispensed for home administration during their chemotherapy appointment.

Patients were included if they received filgrastim for primary prophylaxis of FN with a curative cancer diagnosis. Patients receiving salvage chemotherapy for hematologic malignancies with intent to proceed to curative transplant were also included. Bone marrow involvement of the tumor is a FN risk factor. Only patients with hematologic malignancies and bone marrow involvement were included. Patients wereexcluded if they received filgrastim for secondary prophylaxis of neutropenia or FN, a noncurative cancer diagnosis, stem cell transplant mobilization and engraftment, or nononcologic neutropenia.

The primary outcome for this study was the incidence of neutropenia or FN leading to treatment delays despite the use of primary prophylaxis with filgrastim. A dose delay was defined as a delay of planned chemotherapy by ≥ 3 days. Secondary outcomes included chemotherapy dose decreases or discontinuations, hospitalizations, days of hospitalization, infections, extended duration of filgrastim, and transitions to pegfilgrastim due to neutropenia or FN. Documented infections were defined in patients with a positive culture, laboratory testing, or imaging consistent with infection. Extended durations of filgrastim or transitions to pegfilgrastim were patient specific and upon clinician discretion.

Descriptive statistics were used to summarize the study population and their health outcomes. Fisher exact test was used to compare FN incidence for high- and intermediate-risk FN groups.

RESULTS

Between September 1, 2015, and September 24, 2020, 381 patients received filgrastim. Of these patients, 59 met the inclusion criteria. Patients receiving filgrastim were excluded due to stem cell transplant mobilization/engraftment (n = 145), a noncurative cancer diagnosis (n = 134), use as a secondary prophylaxis (n = 33), and nononcologic neutropenia (n = 8). Additionally, 2 patients initially received pegfilgrastim and were not included in this data set.

The median (IQR) age was 64 (55-70) years and 42 patients (71%) were male (Table 1).

Ten patients (17%) experienced dose delays despite filgrastim use (Table 2).

DISCUSSION

Real-world data are limited regarding G-CSF practice patterns; however, available data demonstrate patients may receive suboptimal treatment courses of filgrastim leading to increased complications associated with neutropenia and FN, such as dose delays and hospitalizations.^8,9 At the South Texas Veterans Health Care System, 48 patients (81%) received a filgrastim course of ≥ 7 days as an initial course for primary prophylaxis. Multivariate analyses performed by Weycker and colleagues described a decreased risk of hospitalization for neutropenia or FN with each additional day of filgrastim prophylaxis; however, such analysis could not be performed in our data set due to the small sample size.⁸ In this review, 10 patients (17%) experienced treatment delays due to neutropenia or FN, mirroring previously published data. The hospitalization rate of 25% is higher than the published incidence of 5.2% of cancer-related hospitalizations among adults.^7,10 This difference may be explained by a difference in health care access for the veteran population.

As an alternative to daily filgrastim injections, the National Comprehensive Cancer Network also recommends a single dose of pegfilgrastim for primary prevention of FN. Efficacy benefits of pegfilgrastim use include increased patient adherence due to a single injection, a reduction in FN incidence and FN-related hospitalizations, and improved time to ANC recovery compared with filgrastim.¹¹ There are reports suggesting pegfilgrastim significantly reduces neutropenia and FN incidence to a greater extent compared with daily filgrastim injections.⁶ In patients with breast cancer receiving dose-dense adjuvant chemotherapy, there are data demonstrating that patients who received filgrastim were more likely to experience severe neutropenia, dose reductions, and treatment delays leading to lower dose density compared with pegfilgrastim.¹² Of the 19 patients with breast cancer included in our population, 26% experienced one of the previously described outcomes leading to either extensions of daily filgrastim injections or transitions to pegfilgrastim to successfully maintain dose density. In patients with acute myeloid leukemia receiving consolidation chemotherapy, filgrastim was found to be associated with a statistically significant increased risk of hospitalizations compared with pegfilgrastim.¹³ The one patient with acute myeloid leukemia included in our study did not require additional hospitalizations for neutropenia or FN after transitioning to pegfilgrastim.

Given the cost advantage, the South Texas Veterans Health Care System continues to prefer daily filgrastim injections. A recent survey demonstrated that 73% of patients at 23 sites in the Veterans Health Administration used filgrastim rather than pegfilgrastim for cost savings, although it is recognized that daily filgrastim injections are less convenient for patients.¹⁴ This analysis did not review costs associated with hospitalization for FN or the appropriateness of G-CSF use. Cancer-related neutropenia accounts for 8.3% of all cancer-related hospitalization costs among adults; the average hospitalization costs nearly $25,000 per stay and about $2.3 billion among adult patients with cancer annually.^10,15

Limitations

This study has limitations that affected the applicability and interpretation of the results. This included the study design since it was a retrospective, single-center, descriptive cohort study. Patient adherence to daily filgrastim injections could not be assessed due to the retrospective nature of the study. The small sample size of 59 patients was prohibitive for utilization of additional analytical tools. Additionally, the predominately male veteran population may make applicability to non-VA populations restrictive.

CONCLUSIONS

Based on the incidence of primary and secondary outcomes associated with using daily filgrastim injections as primary prophylaxis in this study, additional measures such as tracking postnadir ANCs should be performed to ensure patients receive an appropriate number of filgrastim doses to prevent complications associated with neutropenia.

Acknowledgments

We thank Eric Dougherty, PharmD, for assistance in producing granulocyte colony-stimulating factor data.

Febrile neutropenia (FN) frequently occurs in patients receiving chemotherapy, with the greatest risk of complications occurring in those who experience profound and prolonged neutropenia. Although granulocyte colony-stimulating factor (G-CSF) prophylaxis has been shown to reduce the risk and duration of chemotherapy-induced neutropenia and FN, there is no well-established optimal regimen.¹ The 2022 National Comprehensive Cancer Network guidelines for hematopoietic growth factors recommend prophylaxis with G-CSF in at-risk patients receiving chemotherapy, specifically in chemotherapy regimens considered high risk for FN (incidence > 20%) or intermediate risk for FN (incidence 10%-20%) with additional patient risk factors.² The incidence of developing FN with at least 1 chemotherapy cycle is estimated at 10% to 50% of patients with solid tumors and > 80% of patients with hematologic malignancies.³ The rate of major complications (eg, hypotension, acute renal, respiratory, or heart failure) in the context of FN is 25% to 30%, and mortality is reported up to 11% in this population.⁴

Because of the significant consequences of neutropenia and FN, prevention is imperative due to the increase in morbidity and mortality, including chemotherapy delays, increased hospitalizations, chemotherapy dose reductions, and discontinuations that cause delays in care.⁵ In patients with curative malignancies, these consequences can negatively impact treatment efficacy and overall survival. Additionally, infections occur in 20% to 30% of patients with febrile episodes. Although fever is often the only clinical sign or symptom of infection, patients who are profoundly neutropenic may present with suspected infection and be afebrile or hypothermic.³

For filgrastim, the National Comprehensive Cancer Network guidelines do not specify the total days of required injections but state that a daily dose should be given until the postnadir absolute neutrophil count (ANC) recovers to normal or near normal levels by laboratory standards.² It is uncommon in clinical practice to track postnadir ANCs due to frequent laboratory monitoring. Clinical trial data suggest an average duration of 11 days of daily filgrastim injections for ANC recovery; however, real-world data exist supporting a range from 4 to 10 days with a median of 7 injections per cycle for prevention of neutropenia or FN.^6,7

At the South Texas Veterans Health Care System in San Antonio, daily filgrastim injections are preferred due to cost; patients typically receive a 7-day course for primary prophylaxis for FN. In our study, we aimed to determine the outcomes in patients receiving daily filgrastim injections with a curative cancer diagnosis and a chemotherapy regimen with either high risk for FN, or a chemotherapy regimen with an intermediate risk for FN and additional patient risk factors. Before the initiation of data collection, this study was reviewed and determined to be exempt by the University of Texas Health Science Center at San Antonio Institutional Review Board.

METHODS

Electronic health record reviews at the South Texas Veterans Health Care System were performed to identify patients who received filgrastim primary prophylaxis (defined as filgrastim, tbo-filgrastim, or filgrastim-sndz) for a curative cancer diagnosis. Primary prophylaxis refers to the administration of G-CSF in the first cycle of chemotherapy before the onset of neutropenia. Patients received filgrastim prophylaxis if they were undergoing treatment with a chemotherapy regimen with either high risk for FN or a chemotherapy regimen with an intermediate risk for FN and additional patient risk factors. Risk factors for patients included prior chemotherapy or radiation therapy; persistent neutropenia; bone marrow involvement by tumor; recent surgery and/or open wounds; liver dysfunction (defined as total bilirubin > 2 mg/dL); renal dysfunction (defined as creatinine clearance < 50 mL/min); and those aged > 65 years receiving full chemotherapy dose intensity. Neutropenia is defined as a decrease in ANC < 1000 neutrophils/μL, whereas FN is defined as a single temperature of > 38.3 °C or > 38.0 °C for longer than 1 hour with < 500 neutrophils/μL or < 1000 neutrophils/μL predicted to decline to < 500 neutrophils/μL over the next 48 hours. All patients had their filgrastim dispensed for home administration during their chemotherapy appointment.

Patients were included if they received filgrastim for primary prophylaxis of FN with a curative cancer diagnosis. Patients receiving salvage chemotherapy for hematologic malignancies with intent to proceed to curative transplant were also included. Bone marrow involvement of the tumor is a FN risk factor. Only patients with hematologic malignancies and bone marrow involvement were included. Patients wereexcluded if they received filgrastim for secondary prophylaxis of neutropenia or FN, a noncurative cancer diagnosis, stem cell transplant mobilization and engraftment, or nononcologic neutropenia.

The primary outcome for this study was the incidence of neutropenia or FN leading to treatment delays despite the use of primary prophylaxis with filgrastim. A dose delay was defined as a delay of planned chemotherapy by ≥ 3 days. Secondary outcomes included chemotherapy dose decreases or discontinuations, hospitalizations, days of hospitalization, infections, extended duration of filgrastim, and transitions to pegfilgrastim due to neutropenia or FN. Documented infections were defined in patients with a positive culture, laboratory testing, or imaging consistent with infection. Extended durations of filgrastim or transitions to pegfilgrastim were patient specific and upon clinician discretion.

Descriptive statistics were used to summarize the study population and their health outcomes. Fisher exact test was used to compare FN incidence for high- and intermediate-risk FN groups.

RESULTS

Between September 1, 2015, and September 24, 2020, 381 patients received filgrastim. Of these patients, 59 met the inclusion criteria. Patients receiving filgrastim were excluded due to stem cell transplant mobilization/engraftment (n = 145), a noncurative cancer diagnosis (n = 134), use as a secondary prophylaxis (n = 33), and nononcologic neutropenia (n = 8). Additionally, 2 patients initially received pegfilgrastim and were not included in this data set.

The median (IQR) age was 64 (55-70) years and 42 patients (71%) were male (Table 1).

Ten patients (17%) experienced dose delays despite filgrastim use (Table 2).

DISCUSSION

Real-world data are limited regarding G-CSF practice patterns; however, available data demonstrate patients may receive suboptimal treatment courses of filgrastim leading to increased complications associated with neutropenia and FN, such as dose delays and hospitalizations.^8,9 At the South Texas Veterans Health Care System, 48 patients (81%) received a filgrastim course of ≥ 7 days as an initial course for primary prophylaxis. Multivariate analyses performed by Weycker and colleagues described a decreased risk of hospitalization for neutropenia or FN with each additional day of filgrastim prophylaxis; however, such analysis could not be performed in our data set due to the small sample size.⁸ In this review, 10 patients (17%) experienced treatment delays due to neutropenia or FN, mirroring previously published data. The hospitalization rate of 25% is higher than the published incidence of 5.2% of cancer-related hospitalizations among adults.^7,10 This difference may be explained by a difference in health care access for the veteran population.

As an alternative to daily filgrastim injections, the National Comprehensive Cancer Network also recommends a single dose of pegfilgrastim for primary prevention of FN. Efficacy benefits of pegfilgrastim use include increased patient adherence due to a single injection, a reduction in FN incidence and FN-related hospitalizations, and improved time to ANC recovery compared with filgrastim.¹¹ There are reports suggesting pegfilgrastim significantly reduces neutropenia and FN incidence to a greater extent compared with daily filgrastim injections.⁶ In patients with breast cancer receiving dose-dense adjuvant chemotherapy, there are data demonstrating that patients who received filgrastim were more likely to experience severe neutropenia, dose reductions, and treatment delays leading to lower dose density compared with pegfilgrastim.¹² Of the 19 patients with breast cancer included in our population, 26% experienced one of the previously described outcomes leading to either extensions of daily filgrastim injections or transitions to pegfilgrastim to successfully maintain dose density. In patients with acute myeloid leukemia receiving consolidation chemotherapy, filgrastim was found to be associated with a statistically significant increased risk of hospitalizations compared with pegfilgrastim.¹³ The one patient with acute myeloid leukemia included in our study did not require additional hospitalizations for neutropenia or FN after transitioning to pegfilgrastim.

Given the cost advantage, the South Texas Veterans Health Care System continues to prefer daily filgrastim injections. A recent survey demonstrated that 73% of patients at 23 sites in the Veterans Health Administration used filgrastim rather than pegfilgrastim for cost savings, although it is recognized that daily filgrastim injections are less convenient for patients.¹⁴ This analysis did not review costs associated with hospitalization for FN or the appropriateness of G-CSF use. Cancer-related neutropenia accounts for 8.3% of all cancer-related hospitalization costs among adults; the average hospitalization costs nearly $25,000 per stay and about $2.3 billion among adult patients with cancer annually.^10,15

Limitations

This study has limitations that affected the applicability and interpretation of the results. This included the study design since it was a retrospective, single-center, descriptive cohort study. Patient adherence to daily filgrastim injections could not be assessed due to the retrospective nature of the study. The small sample size of 59 patients was prohibitive for utilization of additional analytical tools. Additionally, the predominately male veteran population may make applicability to non-VA populations restrictive.

CONCLUSIONS

Based on the incidence of primary and secondary outcomes associated with using daily filgrastim injections as primary prophylaxis in this study, additional measures such as tracking postnadir ANCs should be performed to ensure patients receive an appropriate number of filgrastim doses to prevent complications associated with neutropenia.

Acknowledgments

We thank Eric Dougherty, PharmD, for assistance in producing granulocyte colony-stimulating factor data.

Radiation therapy can cause long-term dysphagia that seriously affects quality of life for survivors of head and neck cancer. ^1-3 Numerous studies have linked pharyngeal constrictor dose to long-term dysphagia, but conclusions about the dose distribution that can be safely tolerated have been inconsistent. For example, a group from the Netherlands found that the mean dose to the superior pharyngeal constrictor muscle and the supraglottic larynx were each predictive of dysphagia. ⁴ A subsequent Vanderbilt study refuted these findings, reporting that these structures were not predictive but that dose to the inferior pharyngeal constrictor muscle was. ⁵ Other studies have connected late dysphagia with dose to the middle pharyngeal constrictor muscle, total larynx, oral cavity, contralateral submandibular gland, contralateral parotid gland, or a combination of these structures. ^6-14 NRG Oncology trials commonly evaluate dose to the “uninvolved pharynx,” which is the total pharyngeal constrictor muscle volume minus the planning target volume (PTV) for the lowest dose target volume. NRG head and neck trials 3, 4, 5, 6, 8, and 9 all use uninvolved pharynx mean dose ≤ 45 Gy as a constraint to judge radiation plan quality.

Differences in methodology or patient population may explain the inconsistency of prior studies on dosimetric predictors of dysphagia, but it is possible that these studies did not evaluate the optimal metric for dysphagia. This study evaluates a novel organ at risk, the contralateral pharyngeal constrictor muscle, to determine whether dose to this structure is predictive of late swallowing function. The study also compares a constraint based on this structure to the NRG uninvolved pharynx constraint mentioned earlier.

Methods

This study is a retrospective review of patients treated at the Richard L. Roudebush Veterans Affairs (VA) Medical Center in Indianapolis, Indiana. Patients were identified by searching the VA Cancer Registry for patients treated for head and neck squamous cell carcinoma between September 1, 2016, and August 30, 2019. Eligible sites included cancers of the nasopharynx, oropharynx, hypopharynx, larynx and oral cavity, as well as head and neck cancer of an unknown primary site. Only patients treated with primary radiation with concurrent systemic therapy were included. Patients were excluded if they had prior surgery or radiation to the head and neck.

The pharyngeal constrictor muscles were contoured per the techniques described by Bhide and colleagues.¹¹ The contralateral constrictor was defined as the half of the constrictor volume contralateral to the primary site. For midline tumors, the side of the neck with a lower volume of lymph node metastases was judged to be the contralateral side.

Results

The VA Cancer Registry identified 113 patients treated for head and neck cancer during the study period. Of these, 55 patients met the inclusion criteria. No patients were lost to follow-up. The median follow-up was 29 months. The median age was 67 years (range, 41-83) (Table 1).

All patients were treated with intensity-modulated radiotherapy. Patients treated with a sequential boost had an initial dose of 54 Gy and/or 50 Gy, followed by a boost to a total of 70 Gy at 2 Gy per fraction. Patients treated with a simultaneous integrated boost (SIB) technique received 70.0 Gy in 33 fractions, with elective volumes treated to 54.5 Gy in 33 fractions. Both patients with nasopharyngeal cancer were treated with SIB plans and had an intermediate dose volume of 59.4 Gy.

Systemic therapy was weekly cisplatin in 41 patients (75%) and cetuximab in 14 (25%). Twenty percent of patients receiving cisplatin switched to an alternative agent during treatment, most commonly carboplatin.

Forty-nine patients (89%) had a G-tube placed before starting radiation. G-tubes were in place for an interval of 0 to 47 months (mean, 8.6); 12 (22%) had a G-tube > 12 months. After completion of radiation, 18 patients (33%) had an abnormal MBS. These were done 1 to 50 months (mean, 14.8) after completion of radiation. Abnormal MBS occurred ≥ 12 months after radiation in 9 patients, 5 of whom had their G-tube in place for less than a year.

Forty-six patients (84%) survived more than 1 year and could be evaluated for late swallowing function. One-year dysphagia was seen in 17 (37%) of these patients. Recurrence was seen in 20 patients (36%), with locoregional recurrence in 12 (60%) of these cases. Recurrence occurred at a range of 0 to 15 months (mean, 5.6). Neither recurrence (P = .69) nor locoregional recurrence (P = .11) was associated with increased dysphagia at 1 year.

In patients who could be evaluated for long-term swallowing function, contralateral constrictor V60 ranged from 0% to 100% (median, 51%). V60 was < 40% in 18 patients (39%). With V60 < 40%, there was a 6% rate of 1-year dysphagia compared with 57% for V60 ≥ 40% (P < .001).

Patients with contralateral constrictor V60 < 40 and V60 ≥ 40 both had a mean age of 65 years. χ² analysis did not show a difference in T stage or systemic treatment but did show that patients with V60 < 40% were more likely to have N1 disease (P = .01), and less likely to have N2 disease (P = .01) compared with patients with V60 ≥ 40%. The difference in 1-year dysphagia between N0 to N1 patients (27%) and N2 to N3 patients (46%) was not statistically significant (P = .19).

In patients who could be evaluated for long-term swallowing function, the uninvolved pharynx volume median of the total constrictor volume was 32% (range, < 1%-62%). The uninvolved pharynx mean dose ranged from 28 to 68 Gy (median, 45). When the uninvolved pharynx mean dose was < 45 Gy, 1-year dysphagia was 22% compared with 52% with a dose ≥ 45 Gy (P = .03).

Discussion

This is the first study to link contralateral constrictor dose to long-term dysphagia in patients treated with radiation for head and neck cancer. Editing the boost volume off air cavities was associated with lower contralateral constrictor V60 and with less long-term dysphagia. This may indicate that optimizing plans to meet a contralateral constrictor constraint can reduce rates of long-term dysphagia.

The most useful clinical predictors are those that identify a patient at low risk for toxicity. These constraints are useful because they reassure physicians that treatments will have a favorable risk/benefit ratio while identifying plans that may need modification before starting treatment.

The contralateral constrictor outperformed the uninvolved pharynx in identifying patients at low risk for long-term dysphagia. This difference could not be overcome by decreasing the threshold of the pharynx constraint, as 17% of patients with dysphagia had a mean dose of < 40 Gy to the uninvolved pharynx, which was not statistically significant. An advantage of contralateral constrictor is that it is independent of PTV size. The uninvolved pharynx structure depends on the PTV contour, so it may obscure a connection between PTV size and dysphagia.

In the context of a clinical trial, only measuring dose to the uninvolved pharynx may allow more plans to meet constraints, but even in NRG trials, physicians have some control over target volumes. For example, NRG HN009, a national trial for patients with head and neck cancer, recommends editing the CTV_7000 (clinical target volume treated to 70 Gy) off air cavities but does not define how much the volume should be cropped or specify protocol violations if the volume is not cropped.¹⁵ Furthermore, constraints used in clinical trials are often adopted for use outside the trial, where physicians have extensive control over target volumes.

The broad range of uninvolved pharynx volume relative to total constrictor volume confounds predictions using this variable. For example, according to the NRG constraint, a patient with an uninvolved pharynx mean dose of 44 Gy will have a low risk of dysphagia even if this structure is only 1% of the total constrictor. The contralateral constrictor is always about 50% of the total constrictor volume, which means that predictions using this structure will not be confounded by the same variation in volume size.

Figure 2 shows a representative patient who met the NRG uninvolved pharynx constraint but developed long-term dysphagia.

Limitations

This study is limited by its single institution, retrospective design, small sample size, and by all patients being male. The high correlation between air cavity editing and the use of SIB makes it impossible to assess the impact of each technique individually. Patients with contralateral constrictor V60 < 40% were less likely to have N2 disease, but N2 to N3 disease did not predict higher 1-year dysphagia, so the difference in N-category cannot fully explain the difference in 1-year dysphagia. It is possible that unreported factors, such as CTV, may contribute significantly to swallowing function. Nevertheless, within the study population, contralateral constrictor dose was able to identify a group with a low rate of long-term dysphagia.

Conclusions

Contralateral constrictor dose is a promising predictor of late dysphagia for patients with head and neck cancer treated with radiation with concurrent systemic therapy. Contralateral constrictor V60 < 40% was able to identify a group of patients with a low rate of 1-year dysphagia in this single-center retrospective study. The correlation between air cavity editing and contralateral constrictor V60 suggests that contralateral constrictor dose may depend partly on technique. Further studies are needed to see if the contralateral constrictor dose can be used to predict long-term dysphagia prospectively and in other patient populations.

Radiation therapy can cause long-term dysphagia that seriously affects quality of life for survivors of head and neck cancer. ^1-3 Numerous studies have linked pharyngeal constrictor dose to long-term dysphagia, but conclusions about the dose distribution that can be safely tolerated have been inconsistent. For example, a group from the Netherlands found that the mean dose to the superior pharyngeal constrictor muscle and the supraglottic larynx were each predictive of dysphagia. ⁴ A subsequent Vanderbilt study refuted these findings, reporting that these structures were not predictive but that dose to the inferior pharyngeal constrictor muscle was. ⁵ Other studies have connected late dysphagia with dose to the middle pharyngeal constrictor muscle, total larynx, oral cavity, contralateral submandibular gland, contralateral parotid gland, or a combination of these structures. ^6-14 NRG Oncology trials commonly evaluate dose to the “uninvolved pharynx,” which is the total pharyngeal constrictor muscle volume minus the planning target volume (PTV) for the lowest dose target volume. NRG head and neck trials 3, 4, 5, 6, 8, and 9 all use uninvolved pharynx mean dose ≤ 45 Gy as a constraint to judge radiation plan quality.

Differences in methodology or patient population may explain the inconsistency of prior studies on dosimetric predictors of dysphagia, but it is possible that these studies did not evaluate the optimal metric for dysphagia. This study evaluates a novel organ at risk, the contralateral pharyngeal constrictor muscle, to determine whether dose to this structure is predictive of late swallowing function. The study also compares a constraint based on this structure to the NRG uninvolved pharynx constraint mentioned earlier.

Methods

This study is a retrospective review of patients treated at the Richard L. Roudebush Veterans Affairs (VA) Medical Center in Indianapolis, Indiana. Patients were identified by searching the VA Cancer Registry for patients treated for head and neck squamous cell carcinoma between September 1, 2016, and August 30, 2019. Eligible sites included cancers of the nasopharynx, oropharynx, hypopharynx, larynx and oral cavity, as well as head and neck cancer of an unknown primary site. Only patients treated with primary radiation with concurrent systemic therapy were included. Patients were excluded if they had prior surgery or radiation to the head and neck.

The pharyngeal constrictor muscles were contoured per the techniques described by Bhide and colleagues.¹¹ The contralateral constrictor was defined as the half of the constrictor volume contralateral to the primary site. For midline tumors, the side of the neck with a lower volume of lymph node metastases was judged to be the contralateral side.

Results

The VA Cancer Registry identified 113 patients treated for head and neck cancer during the study period. Of these, 55 patients met the inclusion criteria. No patients were lost to follow-up. The median follow-up was 29 months. The median age was 67 years (range, 41-83) (Table 1).

All patients were treated with intensity-modulated radiotherapy. Patients treated with a sequential boost had an initial dose of 54 Gy and/or 50 Gy, followed by a boost to a total of 70 Gy at 2 Gy per fraction. Patients treated with a simultaneous integrated boost (SIB) technique received 70.0 Gy in 33 fractions, with elective volumes treated to 54.5 Gy in 33 fractions. Both patients with nasopharyngeal cancer were treated with SIB plans and had an intermediate dose volume of 59.4 Gy.

Systemic therapy was weekly cisplatin in 41 patients (75%) and cetuximab in 14 (25%). Twenty percent of patients receiving cisplatin switched to an alternative agent during treatment, most commonly carboplatin.

Forty-nine patients (89%) had a G-tube placed before starting radiation. G-tubes were in place for an interval of 0 to 47 months (mean, 8.6); 12 (22%) had a G-tube > 12 months. After completion of radiation, 18 patients (33%) had an abnormal MBS. These were done 1 to 50 months (mean, 14.8) after completion of radiation. Abnormal MBS occurred ≥ 12 months after radiation in 9 patients, 5 of whom had their G-tube in place for less than a year.

Forty-six patients (84%) survived more than 1 year and could be evaluated for late swallowing function. One-year dysphagia was seen in 17 (37%) of these patients. Recurrence was seen in 20 patients (36%), with locoregional recurrence in 12 (60%) of these cases. Recurrence occurred at a range of 0 to 15 months (mean, 5.6). Neither recurrence (P = .69) nor locoregional recurrence (P = .11) was associated with increased dysphagia at 1 year.

In patients who could be evaluated for long-term swallowing function, contralateral constrictor V60 ranged from 0% to 100% (median, 51%). V60 was < 40% in 18 patients (39%). With V60 < 40%, there was a 6% rate of 1-year dysphagia compared with 57% for V60 ≥ 40% (P < .001).

Patients with contralateral constrictor V60 < 40 and V60 ≥ 40 both had a mean age of 65 years. χ² analysis did not show a difference in T stage or systemic treatment but did show that patients with V60 < 40% were more likely to have N1 disease (P = .01), and less likely to have N2 disease (P = .01) compared with patients with V60 ≥ 40%. The difference in 1-year dysphagia between N0 to N1 patients (27%) and N2 to N3 patients (46%) was not statistically significant (P = .19).

In patients who could be evaluated for long-term swallowing function, the uninvolved pharynx volume median of the total constrictor volume was 32% (range, < 1%-62%). The uninvolved pharynx mean dose ranged from 28 to 68 Gy (median, 45). When the uninvolved pharynx mean dose was < 45 Gy, 1-year dysphagia was 22% compared with 52% with a dose ≥ 45 Gy (P = .03).

Discussion

This is the first study to link contralateral constrictor dose to long-term dysphagia in patients treated with radiation for head and neck cancer. Editing the boost volume off air cavities was associated with lower contralateral constrictor V60 and with less long-term dysphagia. This may indicate that optimizing plans to meet a contralateral constrictor constraint can reduce rates of long-term dysphagia.

The most useful clinical predictors are those that identify a patient at low risk for toxicity. These constraints are useful because they reassure physicians that treatments will have a favorable risk/benefit ratio while identifying plans that may need modification before starting treatment.

The contralateral constrictor outperformed the uninvolved pharynx in identifying patients at low risk for long-term dysphagia. This difference could not be overcome by decreasing the threshold of the pharynx constraint, as 17% of patients with dysphagia had a mean dose of < 40 Gy to the uninvolved pharynx, which was not statistically significant. An advantage of contralateral constrictor is that it is independent of PTV size. The uninvolved pharynx structure depends on the PTV contour, so it may obscure a connection between PTV size and dysphagia.

In the context of a clinical trial, only measuring dose to the uninvolved pharynx may allow more plans to meet constraints, but even in NRG trials, physicians have some control over target volumes. For example, NRG HN009, a national trial for patients with head and neck cancer, recommends editing the CTV_7000 (clinical target volume treated to 70 Gy) off air cavities but does not define how much the volume should be cropped or specify protocol violations if the volume is not cropped.¹⁵ Furthermore, constraints used in clinical trials are often adopted for use outside the trial, where physicians have extensive control over target volumes.

The broad range of uninvolved pharynx volume relative to total constrictor volume confounds predictions using this variable. For example, according to the NRG constraint, a patient with an uninvolved pharynx mean dose of 44 Gy will have a low risk of dysphagia even if this structure is only 1% of the total constrictor. The contralateral constrictor is always about 50% of the total constrictor volume, which means that predictions using this structure will not be confounded by the same variation in volume size.

Figure 2 shows a representative patient who met the NRG uninvolved pharynx constraint but developed long-term dysphagia.

Limitations

This study is limited by its single institution, retrospective design, small sample size, and by all patients being male. The high correlation between air cavity editing and the use of SIB makes it impossible to assess the impact of each technique individually. Patients with contralateral constrictor V60 < 40% were less likely to have N2 disease, but N2 to N3 disease did not predict higher 1-year dysphagia, so the difference in N-category cannot fully explain the difference in 1-year dysphagia. It is possible that unreported factors, such as CTV, may contribute significantly to swallowing function. Nevertheless, within the study population, contralateral constrictor dose was able to identify a group with a low rate of long-term dysphagia.

Conclusions

Contralateral constrictor dose is a promising predictor of late dysphagia for patients with head and neck cancer treated with radiation with concurrent systemic therapy. Contralateral constrictor V60 < 40% was able to identify a group of patients with a low rate of 1-year dysphagia in this single-center retrospective study. The correlation between air cavity editing and contralateral constrictor V60 suggests that contralateral constrictor dose may depend partly on technique. Further studies are needed to see if the contralateral constrictor dose can be used to predict long-term dysphagia prospectively and in other patient populations.

Radiation therapy can cause long-term dysphagia that seriously affects quality of life for survivors of head and neck cancer. ^1-3 Numerous studies have linked pharyngeal constrictor dose to long-term dysphagia, but conclusions about the dose distribution that can be safely tolerated have been inconsistent. For example, a group from the Netherlands found that the mean dose to the superior pharyngeal constrictor muscle and the supraglottic larynx were each predictive of dysphagia. ⁴ A subsequent Vanderbilt study refuted these findings, reporting that these structures were not predictive but that dose to the inferior pharyngeal constrictor muscle was. ⁵ Other studies have connected late dysphagia with dose to the middle pharyngeal constrictor muscle, total larynx, oral cavity, contralateral submandibular gland, contralateral parotid gland, or a combination of these structures. ^6-14 NRG Oncology trials commonly evaluate dose to the “uninvolved pharynx,” which is the total pharyngeal constrictor muscle volume minus the planning target volume (PTV) for the lowest dose target volume. NRG head and neck trials 3, 4, 5, 6, 8, and 9 all use uninvolved pharynx mean dose ≤ 45 Gy as a constraint to judge radiation plan quality.

Differences in methodology or patient population may explain the inconsistency of prior studies on dosimetric predictors of dysphagia, but it is possible that these studies did not evaluate the optimal metric for dysphagia. This study evaluates a novel organ at risk, the contralateral pharyngeal constrictor muscle, to determine whether dose to this structure is predictive of late swallowing function. The study also compares a constraint based on this structure to the NRG uninvolved pharynx constraint mentioned earlier.

Methods

This study is a retrospective review of patients treated at the Richard L. Roudebush Veterans Affairs (VA) Medical Center in Indianapolis, Indiana. Patients were identified by searching the VA Cancer Registry for patients treated for head and neck squamous cell carcinoma between September 1, 2016, and August 30, 2019. Eligible sites included cancers of the nasopharynx, oropharynx, hypopharynx, larynx and oral cavity, as well as head and neck cancer of an unknown primary site. Only patients treated with primary radiation with concurrent systemic therapy were included. Patients were excluded if they had prior surgery or radiation to the head and neck.

The pharyngeal constrictor muscles were contoured per the techniques described by Bhide and colleagues.¹¹ The contralateral constrictor was defined as the half of the constrictor volume contralateral to the primary site. For midline tumors, the side of the neck with a lower volume of lymph node metastases was judged to be the contralateral side.

Results

The VA Cancer Registry identified 113 patients treated for head and neck cancer during the study period. Of these, 55 patients met the inclusion criteria. No patients were lost to follow-up. The median follow-up was 29 months. The median age was 67 years (range, 41-83) (Table 1).

All patients were treated with intensity-modulated radiotherapy. Patients treated with a sequential boost had an initial dose of 54 Gy and/or 50 Gy, followed by a boost to a total of 70 Gy at 2 Gy per fraction. Patients treated with a simultaneous integrated boost (SIB) technique received 70.0 Gy in 33 fractions, with elective volumes treated to 54.5 Gy in 33 fractions. Both patients with nasopharyngeal cancer were treated with SIB plans and had an intermediate dose volume of 59.4 Gy.

Systemic therapy was weekly cisplatin in 41 patients (75%) and cetuximab in 14 (25%). Twenty percent of patients receiving cisplatin switched to an alternative agent during treatment, most commonly carboplatin.

Forty-nine patients (89%) had a G-tube placed before starting radiation. G-tubes were in place for an interval of 0 to 47 months (mean, 8.6); 12 (22%) had a G-tube > 12 months. After completion of radiation, 18 patients (33%) had an abnormal MBS. These were done 1 to 50 months (mean, 14.8) after completion of radiation. Abnormal MBS occurred ≥ 12 months after radiation in 9 patients, 5 of whom had their G-tube in place for less than a year.

Forty-six patients (84%) survived more than 1 year and could be evaluated for late swallowing function. One-year dysphagia was seen in 17 (37%) of these patients. Recurrence was seen in 20 patients (36%), with locoregional recurrence in 12 (60%) of these cases. Recurrence occurred at a range of 0 to 15 months (mean, 5.6). Neither recurrence (P = .69) nor locoregional recurrence (P = .11) was associated with increased dysphagia at 1 year.

In patients who could be evaluated for long-term swallowing function, contralateral constrictor V60 ranged from 0% to 100% (median, 51%). V60 was < 40% in 18 patients (39%). With V60 < 40%, there was a 6% rate of 1-year dysphagia compared with 57% for V60 ≥ 40% (P < .001).

Patients with contralateral constrictor V60 < 40 and V60 ≥ 40 both had a mean age of 65 years. χ² analysis did not show a difference in T stage or systemic treatment but did show that patients with V60 < 40% were more likely to have N1 disease (P = .01), and less likely to have N2 disease (P = .01) compared with patients with V60 ≥ 40%. The difference in 1-year dysphagia between N0 to N1 patients (27%) and N2 to N3 patients (46%) was not statistically significant (P = .19).

In patients who could be evaluated for long-term swallowing function, the uninvolved pharynx volume median of the total constrictor volume was 32% (range, < 1%-62%). The uninvolved pharynx mean dose ranged from 28 to 68 Gy (median, 45). When the uninvolved pharynx mean dose was < 45 Gy, 1-year dysphagia was 22% compared with 52% with a dose ≥ 45 Gy (P = .03).

Discussion

This is the first study to link contralateral constrictor dose to long-term dysphagia in patients treated with radiation for head and neck cancer. Editing the boost volume off air cavities was associated with lower contralateral constrictor V60 and with less long-term dysphagia. This may indicate that optimizing plans to meet a contralateral constrictor constraint can reduce rates of long-term dysphagia.

The most useful clinical predictors are those that identify a patient at low risk for toxicity. These constraints are useful because they reassure physicians that treatments will have a favorable risk/benefit ratio while identifying plans that may need modification before starting treatment.

The contralateral constrictor outperformed the uninvolved pharynx in identifying patients at low risk for long-term dysphagia. This difference could not be overcome by decreasing the threshold of the pharynx constraint, as 17% of patients with dysphagia had a mean dose of < 40 Gy to the uninvolved pharynx, which was not statistically significant. An advantage of contralateral constrictor is that it is independent of PTV size. The uninvolved pharynx structure depends on the PTV contour, so it may obscure a connection between PTV size and dysphagia.

In the context of a clinical trial, only measuring dose to the uninvolved pharynx may allow more plans to meet constraints, but even in NRG trials, physicians have some control over target volumes. For example, NRG HN009, a national trial for patients with head and neck cancer, recommends editing the CTV_7000 (clinical target volume treated to 70 Gy) off air cavities but does not define how much the volume should be cropped or specify protocol violations if the volume is not cropped.¹⁵ Furthermore, constraints used in clinical trials are often adopted for use outside the trial, where physicians have extensive control over target volumes.

The broad range of uninvolved pharynx volume relative to total constrictor volume confounds predictions using this variable. For example, according to the NRG constraint, a patient with an uninvolved pharynx mean dose of 44 Gy will have a low risk of dysphagia even if this structure is only 1% of the total constrictor. The contralateral constrictor is always about 50% of the total constrictor volume, which means that predictions using this structure will not be confounded by the same variation in volume size.

Figure 2 shows a representative patient who met the NRG uninvolved pharynx constraint but developed long-term dysphagia.

Limitations

This study is limited by its single institution, retrospective design, small sample size, and by all patients being male. The high correlation between air cavity editing and the use of SIB makes it impossible to assess the impact of each technique individually. Patients with contralateral constrictor V60 < 40% were less likely to have N2 disease, but N2 to N3 disease did not predict higher 1-year dysphagia, so the difference in N-category cannot fully explain the difference in 1-year dysphagia. It is possible that unreported factors, such as CTV, may contribute significantly to swallowing function. Nevertheless, within the study population, contralateral constrictor dose was able to identify a group with a low rate of long-term dysphagia.

Conclusions

Contralateral constrictor dose is a promising predictor of late dysphagia for patients with head and neck cancer treated with radiation with concurrent systemic therapy. Contralateral constrictor V60 < 40% was able to identify a group of patients with a low rate of 1-year dysphagia in this single-center retrospective study. The correlation between air cavity editing and contralateral constrictor V60 suggests that contralateral constrictor dose may depend partly on technique. Further studies are needed to see if the contralateral constrictor dose can be used to predict long-term dysphagia prospectively and in other patient populations.

Thoracic Oncology and Chest Procedures Network

Lung Cancer Section

The mortality benefit associated with lung cancer screening (LCS) using low dose CT (LDCT) relies, in large part, on adherence rates to annual screening of ≥90%. However, the first 1 million “real world” patients screened in the US had very low (22%) annual adherence (Silvestri, et al. Chest. 2023;S0012-3692[23]00175-7). Refining how we estimate future lung cancer risk is an important opportunity for personalized medicine to bolster adherence to follow-up after initial LDCT.

Researchers at MIT developed Sybil, a deep learning algorithm using radiomics on LDCT for LCS to accurately predict 6-year lung cancer risk (Mikhael, et al. J Clin Oncol. 2023;JCO2201345). The model was developed, trained, and tested in a total of 14,185 National Lung Screening Trial (NLST) participants including all cancer diagnoses. Within these data, Sybil’s accuracy in predicting 1-year lung cancer risk had AUC 0.92 (95% CI, 0.88-0.95) and at 6 years, AUC 0.75 (95% CI, 0.72-0.78).

The model was validated in two large independent LCS datasets, one in the US and one in Taiwan, where an LDCT can be obtained regardless of a personal smoking history. The cancer prevalence in these datasets was 3.4% and 0.9%, respectively. Reassuringly, Sybil’s performance was similar to the NLST data and was maintained in relevant subgroups such as sex, age and smoking history. Furthermore, Sybil reduced the false positive rate in the NLST to 8% at baseline scan, compared with 14% for Lung-RADS 1.0. Sybil’s algorithm, unlike others, has been made publicly available and hopefully will spur further validation and prospective study.

Robert Smyth, MD

Member-at-Large

Thoracic Oncology and Chest Procedures Network

Lung Cancer Section

The mortality benefit associated with lung cancer screening (LCS) using low dose CT (LDCT) relies, in large part, on adherence rates to annual screening of ≥90%. However, the first 1 million “real world” patients screened in the US had very low (22%) annual adherence (Silvestri, et al. Chest. 2023;S0012-3692[23]00175-7). Refining how we estimate future lung cancer risk is an important opportunity for personalized medicine to bolster adherence to follow-up after initial LDCT.

Researchers at MIT developed Sybil, a deep learning algorithm using radiomics on LDCT for LCS to accurately predict 6-year lung cancer risk (Mikhael, et al. J Clin Oncol. 2023;JCO2201345). The model was developed, trained, and tested in a total of 14,185 National Lung Screening Trial (NLST) participants including all cancer diagnoses. Within these data, Sybil’s accuracy in predicting 1-year lung cancer risk had AUC 0.92 (95% CI, 0.88-0.95) and at 6 years, AUC 0.75 (95% CI, 0.72-0.78).

The model was validated in two large independent LCS datasets, one in the US and one in Taiwan, where an LDCT can be obtained regardless of a personal smoking history. The cancer prevalence in these datasets was 3.4% and 0.9%, respectively. Reassuringly, Sybil’s performance was similar to the NLST data and was maintained in relevant subgroups such as sex, age and smoking history. Furthermore, Sybil reduced the false positive rate in the NLST to 8% at baseline scan, compared with 14% for Lung-RADS 1.0. Sybil’s algorithm, unlike others, has been made publicly available and hopefully will spur further validation and prospective study.

Robert Smyth, MD

Member-at-Large

Thoracic Oncology and Chest Procedures Network

Lung Cancer Section

The mortality benefit associated with lung cancer screening (LCS) using low dose CT (LDCT) relies, in large part, on adherence rates to annual screening of ≥90%. However, the first 1 million “real world” patients screened in the US had very low (22%) annual adherence (Silvestri, et al. Chest. 2023;S0012-3692[23]00175-7). Refining how we estimate future lung cancer risk is an important opportunity for personalized medicine to bolster adherence to follow-up after initial LDCT.

Researchers at MIT developed Sybil, a deep learning algorithm using radiomics on LDCT for LCS to accurately predict 6-year lung cancer risk (Mikhael, et al. J Clin Oncol. 2023;JCO2201345). The model was developed, trained, and tested in a total of 14,185 National Lung Screening Trial (NLST) participants including all cancer diagnoses. Within these data, Sybil’s accuracy in predicting 1-year lung cancer risk had AUC 0.92 (95% CI, 0.88-0.95) and at 6 years, AUC 0.75 (95% CI, 0.72-0.78).

The model was validated in two large independent LCS datasets, one in the US and one in Taiwan, where an LDCT can be obtained regardless of a personal smoking history. The cancer prevalence in these datasets was 3.4% and 0.9%, respectively. Reassuringly, Sybil’s performance was similar to the NLST data and was maintained in relevant subgroups such as sex, age and smoking history. Furthermore, Sybil reduced the false positive rate in the NLST to 8% at baseline scan, compared with 14% for Lung-RADS 1.0. Sybil’s algorithm, unlike others, has been made publicly available and hopefully will spur further validation and prospective study.

Robert Smyth, MD

Member-at-Large

Primary hepatic lymphoma (PHL) is a rare, malignant lymphoma of the liver. It differs from the predominantly lymph nodal or splenic involvement associated with other types of lymphoma. It is usually detected incidentally on imaging examination, commonly computed tomography (CT), for nonspecific clinical presentation. However, it has important clinical implications for early diagnosis and treatment as indicated in our case.

Case Presentation

An 84-year-old man presented to the emergency department for evaluation of upper back pain. The patient had a history of hypertension, diabetes mellitus, and was a former smoker. He had normal vital signs, an unremarkable physical examination, and a body mass index of 25. His laboratory studies showed a normal blood cell count and serum chemistry, including serum calcium level and α-fetoprotein, but mildly elevated liver function tests.

The patient’s chest CT angiography showed no evidence of thoracic aortic dissection, penetrating atherosclerotic ulceration, or pulmonary artery embolism. Besides emphysematous changes in the lung, the chest CT was within normal limits.

Discussion

Lymphoma is a tumor that originates from hematopoietic cells typically presented as a circumscribed solid tumor of lymphoid cells.¹ Lymphomas are usually seen in the lymph nodes, spleen, blood, bone marrow, brain, gastrointestinal tract, skin, or other normal structures where lymphoreticular cells exist but very rarely in the liver.² PHL is extremely rare due to the lack of abundant lymphoid tissue in the normal liver.³ It accounts for 0.4% of extra-nodal lymphomas and 0.016% of non-Hodgkin lymphoma.^4-6 The etiology of PHL is unknown but usually it develops in patients with previous liver disease: viral infection (hepatitis B and C, Epstein-Barr, and HIV), autoimmune disease, immunosuppression, or liver cirrhosis.^5-7

The diagnosis of PHL can be challenging due to its rarity, vague clinical features, and nonspecific radiologic findings. The common presenting symptoms are usually vague and include abdominal pain or discomfort, fatigue, jaundice, weight loss, and fever.⁵ Liver biopsy is essential to its diagnosis. The disease course is usually indolent among most patients with PHL. In our case, the patient presented with upper back pain but his condition deteriorated rapidly, likely due to the advanced stage of the disease. Diagnosis of liver lymphoma depends on a liver biopsy that should be compatible with the lymphoma. The criteria for diagnosis of PHL defined by Lei include (1) symptoms caused mainly by liver involvement at presentation; (2) absence of distant lymphadenopathy, palpable clinically at presentation or detected during staging radiologic studies; and (3) absence of leukemic blood involvement in the peripheral blood smear.⁷ Other authors define PHL as having major liver involvement without evidence of extrahepatic involvement for at least 6 months.⁸ In our case, the multiple large lesions of the liver are consistent with advanced stage PHL with retroperitoneal lymph nodes and right lung metastasis. DLBCL is the most common histopathological type of lymphoma (65.9%). Other types have been described less commonly, including diffuse mixed large- and small-cell, lymphoblastic, diffuse histiocytic, mantle cell, and small noncleaved or Burkitt lymphoma.^5-7

Currently, there is no consensus on PHL treatment. The therapeutic options include surgery, chemotherapy, radiation therapy, or a combination of therapies.⁷ Most evidence regarding treatment and tumor response comes from case series, as PHLs are rare. Surgical resection in a series of 8 patients showed a cumulative 1- and 2-year survival rate of 66.7% and 55.6%, respectively.⁹ Chemotherapy is the recommended treatment option for extra-nodal DLBCL, making it a choice also for the treatment of PHL.¹⁰ Page and colleagues demonstrated that combination chemotherapy regimens helped achieve remission for 83.3% of patients.¹¹ Since PHL is chemo-sensitive, most patients are treated with chemotherapy alone or in combination with surgery and radiotherapy. The most common chemotherapy regimen is R-CHOP for CD20-positive B-cell lymphoma. The use of the R-CHOP regimen has been reported to achieve complete remission in primary DLBCL of the liver.¹²

Conclusions

Primary DLBCL of the liver is a very rare disease without specific clinical manifestations, biochemical indicators, or radiologic features except for space-occupying liver lesions. However, patients’ conditions can deteriorate rapidly at an advanced stage, as demonstrated in our case. DLBCL requires a high level of suspicion for its early diagnosis and treatment and should be considered in the differential diagnosis for any hepatic space-occupying lesions.

Acknowledgments

We appreciate Lynne Dryer, ARNP, for her clinical assistance with this patient and in the preparation of the manuscript.

Primary hepatic lymphoma (PHL) is a rare, malignant lymphoma of the liver. It differs from the predominantly lymph nodal or splenic involvement associated with other types of lymphoma. It is usually detected incidentally on imaging examination, commonly computed tomography (CT), for nonspecific clinical presentation. However, it has important clinical implications for early diagnosis and treatment as indicated in our case.

Case Presentation

An 84-year-old man presented to the emergency department for evaluation of upper back pain. The patient had a history of hypertension, diabetes mellitus, and was a former smoker. He had normal vital signs, an unremarkable physical examination, and a body mass index of 25. His laboratory studies showed a normal blood cell count and serum chemistry, including serum calcium level and α-fetoprotein, but mildly elevated liver function tests.

The patient’s chest CT angiography showed no evidence of thoracic aortic dissection, penetrating atherosclerotic ulceration, or pulmonary artery embolism. Besides emphysematous changes in the lung, the chest CT was within normal limits.

Discussion

Lymphoma is a tumor that originates from hematopoietic cells typically presented as a circumscribed solid tumor of lymphoid cells.¹ Lymphomas are usually seen in the lymph nodes, spleen, blood, bone marrow, brain, gastrointestinal tract, skin, or other normal structures where lymphoreticular cells exist but very rarely in the liver.² PHL is extremely rare due to the lack of abundant lymphoid tissue in the normal liver.³ It accounts for 0.4% of extra-nodal lymphomas and 0.016% of non-Hodgkin lymphoma.^4-6 The etiology of PHL is unknown but usually it develops in patients with previous liver disease: viral infection (hepatitis B and C, Epstein-Barr, and HIV), autoimmune disease, immunosuppression, or liver cirrhosis.^5-7

The diagnosis of PHL can be challenging due to its rarity, vague clinical features, and nonspecific radiologic findings. The common presenting symptoms are usually vague and include abdominal pain or discomfort, fatigue, jaundice, weight loss, and fever.⁵ Liver biopsy is essential to its diagnosis. The disease course is usually indolent among most patients with PHL. In our case, the patient presented with upper back pain but his condition deteriorated rapidly, likely due to the advanced stage of the disease. Diagnosis of liver lymphoma depends on a liver biopsy that should be compatible with the lymphoma. The criteria for diagnosis of PHL defined by Lei include (1) symptoms caused mainly by liver involvement at presentation; (2) absence of distant lymphadenopathy, palpable clinically at presentation or detected during staging radiologic studies; and (3) absence of leukemic blood involvement in the peripheral blood smear.⁷ Other authors define PHL as having major liver involvement without evidence of extrahepatic involvement for at least 6 months.⁸ In our case, the multiple large lesions of the liver are consistent with advanced stage PHL with retroperitoneal lymph nodes and right lung metastasis. DLBCL is the most common histopathological type of lymphoma (65.9%). Other types have been described less commonly, including diffuse mixed large- and small-cell, lymphoblastic, diffuse histiocytic, mantle cell, and small noncleaved or Burkitt lymphoma.^5-7

Currently, there is no consensus on PHL treatment. The therapeutic options include surgery, chemotherapy, radiation therapy, or a combination of therapies.⁷ Most evidence regarding treatment and tumor response comes from case series, as PHLs are rare. Surgical resection in a series of 8 patients showed a cumulative 1- and 2-year survival rate of 66.7% and 55.6%, respectively.⁹ Chemotherapy is the recommended treatment option for extra-nodal DLBCL, making it a choice also for the treatment of PHL.¹⁰ Page and colleagues demonstrated that combination chemotherapy regimens helped achieve remission for 83.3% of patients.¹¹ Since PHL is chemo-sensitive, most patients are treated with chemotherapy alone or in combination with surgery and radiotherapy. The most common chemotherapy regimen is R-CHOP for CD20-positive B-cell lymphoma. The use of the R-CHOP regimen has been reported to achieve complete remission in primary DLBCL of the liver.¹²

Conclusions

Primary DLBCL of the liver is a very rare disease without specific clinical manifestations, biochemical indicators, or radiologic features except for space-occupying liver lesions. However, patients’ conditions can deteriorate rapidly at an advanced stage, as demonstrated in our case. DLBCL requires a high level of suspicion for its early diagnosis and treatment and should be considered in the differential diagnosis for any hepatic space-occupying lesions.

Acknowledgments

We appreciate Lynne Dryer, ARNP, for her clinical assistance with this patient and in the preparation of the manuscript.

Primary hepatic lymphoma (PHL) is a rare, malignant lymphoma of the liver. It differs from the predominantly lymph nodal or splenic involvement associated with other types of lymphoma. It is usually detected incidentally on imaging examination, commonly computed tomography (CT), for nonspecific clinical presentation. However, it has important clinical implications for early diagnosis and treatment as indicated in our case.

Case Presentation

An 84-year-old man presented to the emergency department for evaluation of upper back pain. The patient had a history of hypertension, diabetes mellitus, and was a former smoker. He had normal vital signs, an unremarkable physical examination, and a body mass index of 25. His laboratory studies showed a normal blood cell count and serum chemistry, including serum calcium level and α-fetoprotein, but mildly elevated liver function tests.

The patient’s chest CT angiography showed no evidence of thoracic aortic dissection, penetrating atherosclerotic ulceration, or pulmonary artery embolism. Besides emphysematous changes in the lung, the chest CT was within normal limits.

Discussion

Lymphoma is a tumor that originates from hematopoietic cells typically presented as a circumscribed solid tumor of lymphoid cells.¹ Lymphomas are usually seen in the lymph nodes, spleen, blood, bone marrow, brain, gastrointestinal tract, skin, or other normal structures where lymphoreticular cells exist but very rarely in the liver.² PHL is extremely rare due to the lack of abundant lymphoid tissue in the normal liver.³ It accounts for 0.4% of extra-nodal lymphomas and 0.016% of non-Hodgkin lymphoma.^4-6 The etiology of PHL is unknown but usually it develops in patients with previous liver disease: viral infection (hepatitis B and C, Epstein-Barr, and HIV), autoimmune disease, immunosuppression, or liver cirrhosis.^5-7

The diagnosis of PHL can be challenging due to its rarity, vague clinical features, and nonspecific radiologic findings. The common presenting symptoms are usually vague and include abdominal pain or discomfort, fatigue, jaundice, weight loss, and fever.⁵ Liver biopsy is essential to its diagnosis. The disease course is usually indolent among most patients with PHL. In our case, the patient presented with upper back pain but his condition deteriorated rapidly, likely due to the advanced stage of the disease. Diagnosis of liver lymphoma depends on a liver biopsy that should be compatible with the lymphoma. The criteria for diagnosis of PHL defined by Lei include (1) symptoms caused mainly by liver involvement at presentation; (2) absence of distant lymphadenopathy, palpable clinically at presentation or detected during staging radiologic studies; and (3) absence of leukemic blood involvement in the peripheral blood smear.⁷ Other authors define PHL as having major liver involvement without evidence of extrahepatic involvement for at least 6 months.⁸ In our case, the multiple large lesions of the liver are consistent with advanced stage PHL with retroperitoneal lymph nodes and right lung metastasis. DLBCL is the most common histopathological type of lymphoma (65.9%). Other types have been described less commonly, including diffuse mixed large- and small-cell, lymphoblastic, diffuse histiocytic, mantle cell, and small noncleaved or Burkitt lymphoma.^5-7

Currently, there is no consensus on PHL treatment. The therapeutic options include surgery, chemotherapy, radiation therapy, or a combination of therapies.⁷ Most evidence regarding treatment and tumor response comes from case series, as PHLs are rare. Surgical resection in a series of 8 patients showed a cumulative 1- and 2-year survival rate of 66.7% and 55.6%, respectively.⁹ Chemotherapy is the recommended treatment option for extra-nodal DLBCL, making it a choice also for the treatment of PHL.¹⁰ Page and colleagues demonstrated that combination chemotherapy regimens helped achieve remission for 83.3% of patients.¹¹ Since PHL is chemo-sensitive, most patients are treated with chemotherapy alone or in combination with surgery and radiotherapy. The most common chemotherapy regimen is R-CHOP for CD20-positive B-cell lymphoma. The use of the R-CHOP regimen has been reported to achieve complete remission in primary DLBCL of the liver.¹²

Conclusions

Primary DLBCL of the liver is a very rare disease without specific clinical manifestations, biochemical indicators, or radiologic features except for space-occupying liver lesions. However, patients’ conditions can deteriorate rapidly at an advanced stage, as demonstrated in our case. DLBCL requires a high level of suspicion for its early diagnosis and treatment and should be considered in the differential diagnosis for any hepatic space-occupying lesions.

Acknowledgments

We appreciate Lynne Dryer, ARNP, for her clinical assistance with this patient and in the preparation of the manuscript.

Many patients with asymptomatic renal stones can qualify for an active surveillance program, Swiss researchers report at the American Urological Association 2023 Annual Meeting.

Kevin Stritt, MD, chief resident in the urology department at Lausanne University Hospital, said kidney stones often pass without symptoms. But until now, data on the frequency of asymptomatic, spontaneous passage of stones have been lacking.

The new data come from the NOSTONE trial, a prospective, multicenter, double-blind, placebo-controlled randomized trial to assess the efficacy of hydrochlorothiazide in the prevention of recurrence in patients with recurrent calcium-containing kidney stones.

Dr. Stritt and colleagues evaluated the natural history of asymptomatic renal stones during a median follow-up of 35 months. “We found for the first time that a relevant number of kidney stone passages [39%] were asymptomatic, spontaneous stone passages,” Dr. Stritt told this news organization.

All asymptomatic spontaneous stone passages were analyzed in a comparison of the total number of kidney stones on low-dose, nonintravenous contrast CT imaging at the beginning and end of the 3-year follow-up.

Of the 403 stones passed spontaneously, 61% (245) were symptomatic stone passages and 39% (158) were asymptomatic stone passages, Dr. Stritt told this news organization.

Asymptomatic stones were a median size of 2.4 mm, and symptomatic stones were 2.15 mm, which was not significantly different (P = .366), according to the researchers. Dr. Stritt said the spontaneous passage of asymptomatic stones was largely influenced by a higher number of stones on CT imaging at randomization (P = .001) and a lower total stone volume (P = .001).

Ephrem Olweny, MD, an assistant professor of urology and section chief of endourology at Rush University Medical Center in Chicago, said previous studies have found that the rate of spontaneous passage of kidney stones ranges from 3% to 29%.

“But this secondary analysis of data from a prior multicenter prospective randomized trial offers higher-quality data that will be of value in guiding patient counseling,” Dr. Olweny said.

“Observation should be initially offered to these patients. However, patients should be informed that 52% are likely to develop symptoms, and some may indeed opt for preemptive surgical removal,” he added.

David Schulsinger, MD, an associate professor in the department of urology at Stony Brook (N.Y.) University Hospital, said the incidence of kidney stones has been increasing worldwide, affecting approximately 12% of men and 6% of women. Dehydration and diets high in sodium and calcium are major factors, he said.

Patients with a history of stones have a 50% risk of recurrence in the next 5 years, and an 80% risk in their lifetime, he added.

Dr. Schulsinger said the message from the Swiss study is that urologists can be “comfortable” watching small stones, those averaging 2.4 mm or less in size. “But if a patient has a 7- or  8-mm stone, you might be more inclined to manage that patient a little bit more aggressively.”

Roughly half of patients with stones less than 2 mm will pass it in about 8 days, he said. 

Dr. Olweny noted that the study was a secondary analysis of data from a randomized controlled trial that evaluated the efficacy of thiazides in preventing the recurrence of calcium stones. “The original study was not specifically designed to look at asymptomatic stone passage rates for small renal stones, and therefore, the observed rates may not reflect the most precise estimates,” he said.

Dr. Stritt said his group has not studied the size limit of stones that pass spontaneously without symptoms. “This study could serve to construct recurrence prediction models based on medical history and stone burden on CT imaging. More well-designed research on this topic is urgently needed,” he said. “These results should encourage urologists to counsel patients about the possibility of an active surveillance strategy when smaller kidney stones are present.”

The author and independent commentators have reported no relevant financial relationships.

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

Many patients with asymptomatic renal stones can qualify for an active surveillance program, Swiss researchers report at the American Urological Association 2023 Annual Meeting.

Kevin Stritt, MD, chief resident in the urology department at Lausanne University Hospital, said kidney stones often pass without symptoms. But until now, data on the frequency of asymptomatic, spontaneous passage of stones have been lacking.

The new data come from the NOSTONE trial, a prospective, multicenter, double-blind, placebo-controlled randomized trial to assess the efficacy of hydrochlorothiazide in the prevention of recurrence in patients with recurrent calcium-containing kidney stones.

Dr. Stritt and colleagues evaluated the natural history of asymptomatic renal stones during a median follow-up of 35 months. “We found for the first time that a relevant number of kidney stone passages [39%] were asymptomatic, spontaneous stone passages,” Dr. Stritt told this news organization.

All asymptomatic spontaneous stone passages were analyzed in a comparison of the total number of kidney stones on low-dose, nonintravenous contrast CT imaging at the beginning and end of the 3-year follow-up.

Of the 403 stones passed spontaneously, 61% (245) were symptomatic stone passages and 39% (158) were asymptomatic stone passages, Dr. Stritt told this news organization.

Asymptomatic stones were a median size of 2.4 mm, and symptomatic stones were 2.15 mm, which was not significantly different (P = .366), according to the researchers. Dr. Stritt said the spontaneous passage of asymptomatic stones was largely influenced by a higher number of stones on CT imaging at randomization (P = .001) and a lower total stone volume (P = .001).

Ephrem Olweny, MD, an assistant professor of urology and section chief of endourology at Rush University Medical Center in Chicago, said previous studies have found that the rate of spontaneous passage of kidney stones ranges from 3% to 29%.

“But this secondary analysis of data from a prior multicenter prospective randomized trial offers higher-quality data that will be of value in guiding patient counseling,” Dr. Olweny said.

“Observation should be initially offered to these patients. However, patients should be informed that 52% are likely to develop symptoms, and some may indeed opt for preemptive surgical removal,” he added.

David Schulsinger, MD, an associate professor in the department of urology at Stony Brook (N.Y.) University Hospital, said the incidence of kidney stones has been increasing worldwide, affecting approximately 12% of men and 6% of women. Dehydration and diets high in sodium and calcium are major factors, he said.

Patients with a history of stones have a 50% risk of recurrence in the next 5 years, and an 80% risk in their lifetime, he added.

Dr. Schulsinger said the message from the Swiss study is that urologists can be “comfortable” watching small stones, those averaging 2.4 mm or less in size. “But if a patient has a 7- or  8-mm stone, you might be more inclined to manage that patient a little bit more aggressively.”

Roughly half of patients with stones less than 2 mm will pass it in about 8 days, he said. 

Dr. Olweny noted that the study was a secondary analysis of data from a randomized controlled trial that evaluated the efficacy of thiazides in preventing the recurrence of calcium stones. “The original study was not specifically designed to look at asymptomatic stone passage rates for small renal stones, and therefore, the observed rates may not reflect the most precise estimates,” he said.

Dr. Stritt said his group has not studied the size limit of stones that pass spontaneously without symptoms. “This study could serve to construct recurrence prediction models based on medical history and stone burden on CT imaging. More well-designed research on this topic is urgently needed,” he said. “These results should encourage urologists to counsel patients about the possibility of an active surveillance strategy when smaller kidney stones are present.”

The author and independent commentators have reported no relevant financial relationships.

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

Many patients with asymptomatic renal stones can qualify for an active surveillance program, Swiss researchers report at the American Urological Association 2023 Annual Meeting.

Kevin Stritt, MD, chief resident in the urology department at Lausanne University Hospital, said kidney stones often pass without symptoms. But until now, data on the frequency of asymptomatic, spontaneous passage of stones have been lacking.

The new data come from the NOSTONE trial, a prospective, multicenter, double-blind, placebo-controlled randomized trial to assess the efficacy of hydrochlorothiazide in the prevention of recurrence in patients with recurrent calcium-containing kidney stones.

Dr. Stritt and colleagues evaluated the natural history of asymptomatic renal stones during a median follow-up of 35 months. “We found for the first time that a relevant number of kidney stone passages [39%] were asymptomatic, spontaneous stone passages,” Dr. Stritt told this news organization.

All asymptomatic spontaneous stone passages were analyzed in a comparison of the total number of kidney stones on low-dose, nonintravenous contrast CT imaging at the beginning and end of the 3-year follow-up.

Of the 403 stones passed spontaneously, 61% (245) were symptomatic stone passages and 39% (158) were asymptomatic stone passages, Dr. Stritt told this news organization.

Asymptomatic stones were a median size of 2.4 mm, and symptomatic stones were 2.15 mm, which was not significantly different (P = .366), according to the researchers. Dr. Stritt said the spontaneous passage of asymptomatic stones was largely influenced by a higher number of stones on CT imaging at randomization (P = .001) and a lower total stone volume (P = .001).

Ephrem Olweny, MD, an assistant professor of urology and section chief of endourology at Rush University Medical Center in Chicago, said previous studies have found that the rate of spontaneous passage of kidney stones ranges from 3% to 29%.

“But this secondary analysis of data from a prior multicenter prospective randomized trial offers higher-quality data that will be of value in guiding patient counseling,” Dr. Olweny said.

“Observation should be initially offered to these patients. However, patients should be informed that 52% are likely to develop symptoms, and some may indeed opt for preemptive surgical removal,” he added.

David Schulsinger, MD, an associate professor in the department of urology at Stony Brook (N.Y.) University Hospital, said the incidence of kidney stones has been increasing worldwide, affecting approximately 12% of men and 6% of women. Dehydration and diets high in sodium and calcium are major factors, he said.

Patients with a history of stones have a 50% risk of recurrence in the next 5 years, and an 80% risk in their lifetime, he added.

Dr. Schulsinger said the message from the Swiss study is that urologists can be “comfortable” watching small stones, those averaging 2.4 mm or less in size. “But if a patient has a 7- or  8-mm stone, you might be more inclined to manage that patient a little bit more aggressively.”

Roughly half of patients with stones less than 2 mm will pass it in about 8 days, he said. 

Dr. Olweny noted that the study was a secondary analysis of data from a randomized controlled trial that evaluated the efficacy of thiazides in preventing the recurrence of calcium stones. “The original study was not specifically designed to look at asymptomatic stone passage rates for small renal stones, and therefore, the observed rates may not reflect the most precise estimates,” he said.

Dr. Stritt said his group has not studied the size limit of stones that pass spontaneously without symptoms. “This study could serve to construct recurrence prediction models based on medical history and stone burden on CT imaging. More well-designed research on this topic is urgently needed,” he said. “These results should encourage urologists to counsel patients about the possibility of an active surveillance strategy when smaller kidney stones are present.”

The author and independent commentators have reported no relevant financial relationships.

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

Cholangiocarcinoma is a heterogeneous, highly aggressive cancer of the biliary tract epithelium with an overall 5-year relative survival rate of only 9%.^1,2 Although surgical resection of localized, intrahepatic cholangiocarcinoma is associated with improved overall survival, most patients present with advanced disease not amenable to surgery due to a late onset of symptoms.² Recently, an increased incidence of cholangiocarcinoma has been reported in the United States.³ Although relatively rare in the US, cholangiocarcinoma is prevalent across large parts of Asia, including China, Vietnam, Thailand, South Korea, and Taiwan.²

Risk Factors

To date, risk factors for developing cholangiocarcinoma have not been elucidated. ^4,5 However, a growing body of literature suggests that chronic infection of genetically susceptible human subjects with Clonorchis sinensis ( C sinensis ) and Opisthorchis viverrini ( O viverrini ) plays a role. ^6,7 The life cycle of these food-borne zoonotic trematodes involves eggs discharged in the stool of infected humans, the definitive host. ^6,7 In nature, these eggs are ingested by freshwater snails, the intermediate host, where they undergo several developmental stages to form cercariae. Once released from snails into the water, free-swimming cercariae come in contact and penetrate freshwater fish where they encyst as metacercariae. Infection of humans occurs by ingesting undercooked, salted, pickled, or smoked freshwater fish infested with metacercariae. After ingestion, metacercariae excyst in the duodenum and ascend the biliary tract through the ampulla of Vater. They then mature into adult flukes that reside in small- and medium-sized intrahepatic biliary ducts. ^6,7

Although most infected people remain asymptomatic, untreated indolent infections with C sinensis and O viverrini may persist in peripheral intrahepatic bile ducts for as long as 30 years, which is the lifespan of the trematodes.^6,7 During this prolonged period, C sinensis and O viverrini feeding activities and their excretory-secretory products may damage bile duct epithelium and promote intense local inflammation.^6,7 Conceivably, these pathological processes could then provoke the epithelial desquamation, adenomatous hyperplasia, goblet cell metaplasia, periductal fibrosis, and granuloma formation that are conducive to initiation and progression of cholangiocarcinoma in genetically susceptible people.⁸ Accordingly, the International Agency for Research on Cancer (IARC) has determined that there is sufficient evidence for the carcinogenicity of chronic infections with C sinensis and O viverrini in humans and that chronic infections with these trematodes cause cholangiocarcinoma.⁹ The IARC concluded that chronic infections with C sinensis and O viverrini are carcinogenic to humans (Group 1).⁹

Diagnosis

Presently, the diagnosis of C sinensis and O viverrini infection is based on microscopic identification and enumeration of the parasites’ eggs in weighted stool specimens using a formalin-ethyl acetate sedimentation concentration technique. ^6,7 This approach requires a labor-intensive test that is conducted by an experienced technician. The test has low specificity and sensitivity because eggs could be confused with those of nonpathogenic intestinal flukes that are morphologically similar and because eggs are not present in feces during all stages of the infection. Although diffuse dilatation of intrahepatic bile ducts by screening sonography is used to diagnose clonorchiasis in endemic areas, it has low sensitivity, particularly in patients with low-level C sinensis and O viverrin i infections. ¹⁰

To address the current diagnostic gap, several enzyme-linked immunosorbent assays (ELISA) have been developed for the diagnosis of C sinensis, including monoclonal antibody-based (mAb) ELISA and indirect antibody ELISA.^11,12 However, both have important limitations. The mAb ELISA detects only active infections while indirect antibody ELISA cross-reacts with other liver flukes.^11,12 Taken together, these data illustrate the difficulties in diagnosing asymptomatic individuals with low-burden C sinensis or O viverrini infections by existing laboratory methods.

Timely serodiagnosis of indolent C sinensis and O viverrini infections is important because these parasites have recently been raised as a risk factor for cholangiocarcinoma in veterans who served in Vietnam.¹³ The American War Library estimates that as of February 28, 2019, about 610,000 Americans who served on land in Vietnam or in the air over Vietnam between 1954 and 1975 are alive, and about 164,000 Americans who served at sea in Vietnam waters are alive.¹⁴ To that end, Psevdos and colleagues screened 97 US veterans who served in Vietnam and identified 50 who reported exposure to raw or undercooked fish while there.¹³ None had evidence of active C sinensis or O viverrini infection. Blood samples obtained from these veterans were analyzed for circulating C sinensis and O viverrini antibodies using an ELISA developed in South Korea and 12 blood samples tested positive for the trematodes. Imaging of extrahepatic and intrahepatic bile ducts was unyielding in all cases. One veteran diagnosed with cholangiocarcinoma had repeated negative tests. However, the results of this study were challenged by several experts in this field because the authors did not report the sensitivity and specificity of the ELISA assay used.¹⁵

Serologic testing of US veterans who served in C sinensis and O viverrini–endemic countries for indolent infections with these parasites is not recommended at present.¹⁵ Nevertheless, there is an urgent need to develop sensitive and specific serologic assays, such as ELISA tests with recombinant antigens, to detect both acute and indolent infections caused by each biliary liver fluke in the US, including in patients diagnosed with cholangiocarcinoma. We posit that testing and treatment of high-risk populations could lead to earlier detection and treatment of cholangiocarcinoma, leading to improved overall survival in the population at risk.

Cholangiocarcinoma is a heterogeneous, highly aggressive cancer of the biliary tract epithelium with an overall 5-year relative survival rate of only 9%.^1,2 Although surgical resection of localized, intrahepatic cholangiocarcinoma is associated with improved overall survival, most patients present with advanced disease not amenable to surgery due to a late onset of symptoms.² Recently, an increased incidence of cholangiocarcinoma has been reported in the United States.³ Although relatively rare in the US, cholangiocarcinoma is prevalent across large parts of Asia, including China, Vietnam, Thailand, South Korea, and Taiwan.²

Risk Factors

To date, risk factors for developing cholangiocarcinoma have not been elucidated. ^4,5 However, a growing body of literature suggests that chronic infection of genetically susceptible human subjects with Clonorchis sinensis ( C sinensis ) and Opisthorchis viverrini ( O viverrini ) plays a role. ^6,7 The life cycle of these food-borne zoonotic trematodes involves eggs discharged in the stool of infected humans, the definitive host. ^6,7 In nature, these eggs are ingested by freshwater snails, the intermediate host, where they undergo several developmental stages to form cercariae. Once released from snails into the water, free-swimming cercariae come in contact and penetrate freshwater fish where they encyst as metacercariae. Infection of humans occurs by ingesting undercooked, salted, pickled, or smoked freshwater fish infested with metacercariae. After ingestion, metacercariae excyst in the duodenum and ascend the biliary tract through the ampulla of Vater. They then mature into adult flukes that reside in small- and medium-sized intrahepatic biliary ducts. ^6,7

Although most infected people remain asymptomatic, untreated indolent infections with C sinensis and O viverrini may persist in peripheral intrahepatic bile ducts for as long as 30 years, which is the lifespan of the trematodes.^6,7 During this prolonged period, C sinensis and O viverrini feeding activities and their excretory-secretory products may damage bile duct epithelium and promote intense local inflammation.^6,7 Conceivably, these pathological processes could then provoke the epithelial desquamation, adenomatous hyperplasia, goblet cell metaplasia, periductal fibrosis, and granuloma formation that are conducive to initiation and progression of cholangiocarcinoma in genetically susceptible people.⁸ Accordingly, the International Agency for Research on Cancer (IARC) has determined that there is sufficient evidence for the carcinogenicity of chronic infections with C sinensis and O viverrini in humans and that chronic infections with these trematodes cause cholangiocarcinoma.⁹ The IARC concluded that chronic infections with C sinensis and O viverrini are carcinogenic to humans (Group 1).⁹

Diagnosis

Presently, the diagnosis of C sinensis and O viverrini infection is based on microscopic identification and enumeration of the parasites’ eggs in weighted stool specimens using a formalin-ethyl acetate sedimentation concentration technique. ^6,7 This approach requires a labor-intensive test that is conducted by an experienced technician. The test has low specificity and sensitivity because eggs could be confused with those of nonpathogenic intestinal flukes that are morphologically similar and because eggs are not present in feces during all stages of the infection. Although diffuse dilatation of intrahepatic bile ducts by screening sonography is used to diagnose clonorchiasis in endemic areas, it has low sensitivity, particularly in patients with low-level C sinensis and O viverrin i infections. ¹⁰

To address the current diagnostic gap, several enzyme-linked immunosorbent assays (ELISA) have been developed for the diagnosis of C sinensis, including monoclonal antibody-based (mAb) ELISA and indirect antibody ELISA.^11,12 However, both have important limitations. The mAb ELISA detects only active infections while indirect antibody ELISA cross-reacts with other liver flukes.^11,12 Taken together, these data illustrate the difficulties in diagnosing asymptomatic individuals with low-burden C sinensis or O viverrini infections by existing laboratory methods.

Timely serodiagnosis of indolent C sinensis and O viverrini infections is important because these parasites have recently been raised as a risk factor for cholangiocarcinoma in veterans who served in Vietnam.¹³ The American War Library estimates that as of February 28, 2019, about 610,000 Americans who served on land in Vietnam or in the air over Vietnam between 1954 and 1975 are alive, and about 164,000 Americans who served at sea in Vietnam waters are alive.¹⁴ To that end, Psevdos and colleagues screened 97 US veterans who served in Vietnam and identified 50 who reported exposure to raw or undercooked fish while there.¹³ None had evidence of active C sinensis or O viverrini infection. Blood samples obtained from these veterans were analyzed for circulating C sinensis and O viverrini antibodies using an ELISA developed in South Korea and 12 blood samples tested positive for the trematodes. Imaging of extrahepatic and intrahepatic bile ducts was unyielding in all cases. One veteran diagnosed with cholangiocarcinoma had repeated negative tests. However, the results of this study were challenged by several experts in this field because the authors did not report the sensitivity and specificity of the ELISA assay used.¹⁵

Serologic testing of US veterans who served in C sinensis and O viverrini–endemic countries for indolent infections with these parasites is not recommended at present.¹⁵ Nevertheless, there is an urgent need to develop sensitive and specific serologic assays, such as ELISA tests with recombinant antigens, to detect both acute and indolent infections caused by each biliary liver fluke in the US, including in patients diagnosed with cholangiocarcinoma. We posit that testing and treatment of high-risk populations could lead to earlier detection and treatment of cholangiocarcinoma, leading to improved overall survival in the population at risk.

Cholangiocarcinoma is a heterogeneous, highly aggressive cancer of the biliary tract epithelium with an overall 5-year relative survival rate of only 9%.^1,2 Although surgical resection of localized, intrahepatic cholangiocarcinoma is associated with improved overall survival, most patients present with advanced disease not amenable to surgery due to a late onset of symptoms.² Recently, an increased incidence of cholangiocarcinoma has been reported in the United States.³ Although relatively rare in the US, cholangiocarcinoma is prevalent across large parts of Asia, including China, Vietnam, Thailand, South Korea, and Taiwan.²

Risk Factors

To date, risk factors for developing cholangiocarcinoma have not been elucidated. ^4,5 However, a growing body of literature suggests that chronic infection of genetically susceptible human subjects with Clonorchis sinensis ( C sinensis ) and Opisthorchis viverrini ( O viverrini ) plays a role. ^6,7 The life cycle of these food-borne zoonotic trematodes involves eggs discharged in the stool of infected humans, the definitive host. ^6,7 In nature, these eggs are ingested by freshwater snails, the intermediate host, where they undergo several developmental stages to form cercariae. Once released from snails into the water, free-swimming cercariae come in contact and penetrate freshwater fish where they encyst as metacercariae. Infection of humans occurs by ingesting undercooked, salted, pickled, or smoked freshwater fish infested with metacercariae. After ingestion, metacercariae excyst in the duodenum and ascend the biliary tract through the ampulla of Vater. They then mature into adult flukes that reside in small- and medium-sized intrahepatic biliary ducts. ^6,7

Although most infected people remain asymptomatic, untreated indolent infections with C sinensis and O viverrini may persist in peripheral intrahepatic bile ducts for as long as 30 years, which is the lifespan of the trematodes.^6,7 During this prolonged period, C sinensis and O viverrini feeding activities and their excretory-secretory products may damage bile duct epithelium and promote intense local inflammation.^6,7 Conceivably, these pathological processes could then provoke the epithelial desquamation, adenomatous hyperplasia, goblet cell metaplasia, periductal fibrosis, and granuloma formation that are conducive to initiation and progression of cholangiocarcinoma in genetically susceptible people.⁸ Accordingly, the International Agency for Research on Cancer (IARC) has determined that there is sufficient evidence for the carcinogenicity of chronic infections with C sinensis and O viverrini in humans and that chronic infections with these trematodes cause cholangiocarcinoma.⁹ The IARC concluded that chronic infections with C sinensis and O viverrini are carcinogenic to humans (Group 1).⁹

Diagnosis

Presently, the diagnosis of C sinensis and O viverrini infection is based on microscopic identification and enumeration of the parasites’ eggs in weighted stool specimens using a formalin-ethyl acetate sedimentation concentration technique. ^6,7 This approach requires a labor-intensive test that is conducted by an experienced technician. The test has low specificity and sensitivity because eggs could be confused with those of nonpathogenic intestinal flukes that are morphologically similar and because eggs are not present in feces during all stages of the infection. Although diffuse dilatation of intrahepatic bile ducts by screening sonography is used to diagnose clonorchiasis in endemic areas, it has low sensitivity, particularly in patients with low-level C sinensis and O viverrin i infections. ¹⁰

To address the current diagnostic gap, several enzyme-linked immunosorbent assays (ELISA) have been developed for the diagnosis of C sinensis, including monoclonal antibody-based (mAb) ELISA and indirect antibody ELISA.^11,12 However, both have important limitations. The mAb ELISA detects only active infections while indirect antibody ELISA cross-reacts with other liver flukes.^11,12 Taken together, these data illustrate the difficulties in diagnosing asymptomatic individuals with low-burden C sinensis or O viverrini infections by existing laboratory methods.

Timely serodiagnosis of indolent C sinensis and O viverrini infections is important because these parasites have recently been raised as a risk factor for cholangiocarcinoma in veterans who served in Vietnam.¹³ The American War Library estimates that as of February 28, 2019, about 610,000 Americans who served on land in Vietnam or in the air over Vietnam between 1954 and 1975 are alive, and about 164,000 Americans who served at sea in Vietnam waters are alive.¹⁴ To that end, Psevdos and colleagues screened 97 US veterans who served in Vietnam and identified 50 who reported exposure to raw or undercooked fish while there.¹³ None had evidence of active C sinensis or O viverrini infection. Blood samples obtained from these veterans were analyzed for circulating C sinensis and O viverrini antibodies using an ELISA developed in South Korea and 12 blood samples tested positive for the trematodes. Imaging of extrahepatic and intrahepatic bile ducts was unyielding in all cases. One veteran diagnosed with cholangiocarcinoma had repeated negative tests. However, the results of this study were challenged by several experts in this field because the authors did not report the sensitivity and specificity of the ELISA assay used.¹⁵

Serologic testing of US veterans who served in C sinensis and O viverrini–endemic countries for indolent infections with these parasites is not recommended at present.¹⁵ Nevertheless, there is an urgent need to develop sensitive and specific serologic assays, such as ELISA tests with recombinant antigens, to detect both acute and indolent infections caused by each biliary liver fluke in the US, including in patients diagnosed with cholangiocarcinoma. We posit that testing and treatment of high-risk populations could lead to earlier detection and treatment of cholangiocarcinoma, leading to improved overall survival in the population at risk.

A cohort study of more than 1.5 million hospital admissions in Canada through the first 2 years of the COVID-19 pandemic has quantified the benefit of vaccinations. Unvaccinated patients were found to be up to 15 times more likely to die from COVID-19 than fully vaccinated patients.

Investigators analyzed 1.513 million admissions at 155 hospitals across Canada from March 15, 2020, to May 28, 2022. The study included 51,679 adult admissions and 4,035 pediatric admissions for COVID-19. Although the share of COVID-19 admissions increased in the fifth and sixth waves, from Dec. 26, 2021, to March 19, 2022 – after the full vaccine rollout – to 7.73% from 2.47% in the previous four waves, the proportion of adults admitted to the intensive care unit was significantly lower, at 8.7% versus 21.8% (odds ratio, 0.35; 95% confidence interval, 0.32-0.36).

“The good thing about waves five and six was we were able to show the COVID cases tended to be less severe, but on the other hand, because the disease in the community was so much higher, the demands on the health care system were much higher than the previous waves,” study author Charles Frenette, MD, director of infection prevention and control at McGill University, Montreal, and chair of the study’s adult subgroup, said in an interview. “But here we were able to show the benefit of vaccinations, particularly the boosting dose, in protecting against those severe outcomes.”

The study, published  in JAMA Network Open, used the Canadian Nosocomial Infection Surveillance Program database, which collects hospital data across Canada. It was activated in March 2020 to collect details on all COVID-19 admissions, co-author Nisha Thampi, MD, chair of the study’s pediatric subgroup, told this news organization.

“We’re now over 3 years into the pandemic, and CNISP continues to monitor COVID-19 as well as other pathogens in near real time,” said Dr. Thampi, an associate professor and infectious disease specialist at Children’s Hospital of Eastern Ontario.

“That’s a particular strength of this surveillance program as well. We would see this data on a biweekly basis, and that allows for [us] to implement timely protection and action.”
 

Tracing trends over six waves

The study tracked COVID-19 hospitalizations during six waves. The first lasted from March 15 to August 31, 2020, and the second lasted from Sept. 1, 2020, to Feb. 28, 2021. The wild-type variant was dominant during both waves. The third wave lasted from March 1 to June 30, 2021, and was marked by the mixed Alpha, Beta, and Gamma variants. The fourth wave lasted from July 1 to Dec. 25, 2021, when the Alpha variant was dominant. The Omicron variant dominated during waves five (Dec. 26, 2021, to March 19, 2022) and six (March 20 to May 28, 2022).

Hospitalizations reached a peak of 14,461 in wave five. ICU admissions, however, peaked at 2,164 during wave four, and all-cause deaths peaked at 1,663 during wave two.

The investigators also analyzed how unvaccinated patients fared, compared with the fully vaccinated and the fully vaccinated-plus (that is, patients with one or more additional doses). During waves five and six, unvaccinated patients were 4.3 times more likely to end up in the ICU than fully vaccinated patients and were 12.2 times more likely than fully vaccinated-plus patients. Likewise, the rate for all-cause in-hospital death for unvaccinated patients was 3.9 times greater than that for fully vaccinated patients and 15.1 times greater than that for fully vaccinated-plus patients.

The effect of vaccines emerged in waves three and four, said Dr. Frenette. “We started to see really, really significant protection and benefit from the vaccine, not only in incidence of admission but also in the incidence of complications of ICU care, ventilation, and mortality.”

Results for pediatric patients were similar to those for adults, Dr. Thampi noted. During waves five and six, overall admissions peaked, but the share of ICU admissions decreased to 9.4% from 18.1%, which was the rate during the previous four waves (OR, 0.47).

“What’s important is how pediatric hospitalizations changed over the course of the various waves,” said Dr. Thampi.

“Where we saw the highest admissions during the early Omicron dominance, we actually had the lowest numbers of hospitalizations with death and admissions into ICUs.”
 

Doing more with the data

David Fisman, MD, MPH, a professor of epidemiology at the University of Toronto, said, “This is a study that shows us how tremendously dramatic the effects of the COVID-19 vaccine were in terms of saving lives during the pandemic.” Dr. Fisman was not involved in the study.

But CNISP, which receives funding from Public Health Agency of Canada, could do more with the data it collects to better protect the public from COVID-19 and other nosocomial infections, Dr. Fisman said.

“The first problematic thing about this paper is that Canadians are paying for a surveillance system that looks at risks of acquiring infections, including COVID-19 infections, in the hospital, but that data is not fed back to the people paying for its production,” he said.

“So, Canadians don’t have the ability to really understand in real time how much risk they’re experiencing via going to the hospital for some other reason.”

The study was independently supported. Dr. Frenette and Dr. Thampi report no relevant financial relationships. Dr. Fisman has disclosed financial relationships with Pfizer, AstraZeneca, Sanofi, Seqirus, Merck, the Ontario Nurses Association, and the Elementary Teachers’ Federation of Ontario.

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

A cohort study of more than 1.5 million hospital admissions in Canada through the first 2 years of the COVID-19 pandemic has quantified the benefit of vaccinations. Unvaccinated patients were found to be up to 15 times more likely to die from COVID-19 than fully vaccinated patients.

Investigators analyzed 1.513 million admissions at 155 hospitals across Canada from March 15, 2020, to May 28, 2022. The study included 51,679 adult admissions and 4,035 pediatric admissions for COVID-19. Although the share of COVID-19 admissions increased in the fifth and sixth waves, from Dec. 26, 2021, to March 19, 2022 – after the full vaccine rollout – to 7.73% from 2.47% in the previous four waves, the proportion of adults admitted to the intensive care unit was significantly lower, at 8.7% versus 21.8% (odds ratio, 0.35; 95% confidence interval, 0.32-0.36).

“The good thing about waves five and six was we were able to show the COVID cases tended to be less severe, but on the other hand, because the disease in the community was so much higher, the demands on the health care system were much higher than the previous waves,” study author Charles Frenette, MD, director of infection prevention and control at McGill University, Montreal, and chair of the study’s adult subgroup, said in an interview. “But here we were able to show the benefit of vaccinations, particularly the boosting dose, in protecting against those severe outcomes.”

The study, published  in JAMA Network Open, used the Canadian Nosocomial Infection Surveillance Program database, which collects hospital data across Canada. It was activated in March 2020 to collect details on all COVID-19 admissions, co-author Nisha Thampi, MD, chair of the study’s pediatric subgroup, told this news organization.

“We’re now over 3 years into the pandemic, and CNISP continues to monitor COVID-19 as well as other pathogens in near real time,” said Dr. Thampi, an associate professor and infectious disease specialist at Children’s Hospital of Eastern Ontario.

“That’s a particular strength of this surveillance program as well. We would see this data on a biweekly basis, and that allows for [us] to implement timely protection and action.”
 

Tracing trends over six waves

The study tracked COVID-19 hospitalizations during six waves. The first lasted from March 15 to August 31, 2020, and the second lasted from Sept. 1, 2020, to Feb. 28, 2021. The wild-type variant was dominant during both waves. The third wave lasted from March 1 to June 30, 2021, and was marked by the mixed Alpha, Beta, and Gamma variants. The fourth wave lasted from July 1 to Dec. 25, 2021, when the Alpha variant was dominant. The Omicron variant dominated during waves five (Dec. 26, 2021, to March 19, 2022) and six (March 20 to May 28, 2022).

Hospitalizations reached a peak of 14,461 in wave five. ICU admissions, however, peaked at 2,164 during wave four, and all-cause deaths peaked at 1,663 during wave two.

The investigators also analyzed how unvaccinated patients fared, compared with the fully vaccinated and the fully vaccinated-plus (that is, patients with one or more additional doses). During waves five and six, unvaccinated patients were 4.3 times more likely to end up in the ICU than fully vaccinated patients and were 12.2 times more likely than fully vaccinated-plus patients. Likewise, the rate for all-cause in-hospital death for unvaccinated patients was 3.9 times greater than that for fully vaccinated patients and 15.1 times greater than that for fully vaccinated-plus patients.

The effect of vaccines emerged in waves three and four, said Dr. Frenette. “We started to see really, really significant protection and benefit from the vaccine, not only in incidence of admission but also in the incidence of complications of ICU care, ventilation, and mortality.”

Results for pediatric patients were similar to those for adults, Dr. Thampi noted. During waves five and six, overall admissions peaked, but the share of ICU admissions decreased to 9.4% from 18.1%, which was the rate during the previous four waves (OR, 0.47).

“What’s important is how pediatric hospitalizations changed over the course of the various waves,” said Dr. Thampi.

“Where we saw the highest admissions during the early Omicron dominance, we actually had the lowest numbers of hospitalizations with death and admissions into ICUs.”
 

Doing more with the data

David Fisman, MD, MPH, a professor of epidemiology at the University of Toronto, said, “This is a study that shows us how tremendously dramatic the effects of the COVID-19 vaccine were in terms of saving lives during the pandemic.” Dr. Fisman was not involved in the study.

But CNISP, which receives funding from Public Health Agency of Canada, could do more with the data it collects to better protect the public from COVID-19 and other nosocomial infections, Dr. Fisman said.

“The first problematic thing about this paper is that Canadians are paying for a surveillance system that looks at risks of acquiring infections, including COVID-19 infections, in the hospital, but that data is not fed back to the people paying for its production,” he said.

“So, Canadians don’t have the ability to really understand in real time how much risk they’re experiencing via going to the hospital for some other reason.”

The study was independently supported. Dr. Frenette and Dr. Thampi report no relevant financial relationships. Dr. Fisman has disclosed financial relationships with Pfizer, AstraZeneca, Sanofi, Seqirus, Merck, the Ontario Nurses Association, and the Elementary Teachers’ Federation of Ontario.

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

A cohort study of more than 1.5 million hospital admissions in Canada through the first 2 years of the COVID-19 pandemic has quantified the benefit of vaccinations. Unvaccinated patients were found to be up to 15 times more likely to die from COVID-19 than fully vaccinated patients.

Investigators analyzed 1.513 million admissions at 155 hospitals across Canada from March 15, 2020, to May 28, 2022. The study included 51,679 adult admissions and 4,035 pediatric admissions for COVID-19. Although the share of COVID-19 admissions increased in the fifth and sixth waves, from Dec. 26, 2021, to March 19, 2022 – after the full vaccine rollout – to 7.73% from 2.47% in the previous four waves, the proportion of adults admitted to the intensive care unit was significantly lower, at 8.7% versus 21.8% (odds ratio, 0.35; 95% confidence interval, 0.32-0.36).

“The good thing about waves five and six was we were able to show the COVID cases tended to be less severe, but on the other hand, because the disease in the community was so much higher, the demands on the health care system were much higher than the previous waves,” study author Charles Frenette, MD, director of infection prevention and control at McGill University, Montreal, and chair of the study’s adult subgroup, said in an interview. “But here we were able to show the benefit of vaccinations, particularly the boosting dose, in protecting against those severe outcomes.”

The study, published  in JAMA Network Open, used the Canadian Nosocomial Infection Surveillance Program database, which collects hospital data across Canada. It was activated in March 2020 to collect details on all COVID-19 admissions, co-author Nisha Thampi, MD, chair of the study’s pediatric subgroup, told this news organization.

“We’re now over 3 years into the pandemic, and CNISP continues to monitor COVID-19 as well as other pathogens in near real time,” said Dr. Thampi, an associate professor and infectious disease specialist at Children’s Hospital of Eastern Ontario.

“That’s a particular strength of this surveillance program as well. We would see this data on a biweekly basis, and that allows for [us] to implement timely protection and action.”
 

Tracing trends over six waves

The study tracked COVID-19 hospitalizations during six waves. The first lasted from March 15 to August 31, 2020, and the second lasted from Sept. 1, 2020, to Feb. 28, 2021. The wild-type variant was dominant during both waves. The third wave lasted from March 1 to June 30, 2021, and was marked by the mixed Alpha, Beta, and Gamma variants. The fourth wave lasted from July 1 to Dec. 25, 2021, when the Alpha variant was dominant. The Omicron variant dominated during waves five (Dec. 26, 2021, to March 19, 2022) and six (March 20 to May 28, 2022).

Hospitalizations reached a peak of 14,461 in wave five. ICU admissions, however, peaked at 2,164 during wave four, and all-cause deaths peaked at 1,663 during wave two.

The investigators also analyzed how unvaccinated patients fared, compared with the fully vaccinated and the fully vaccinated-plus (that is, patients with one or more additional doses). During waves five and six, unvaccinated patients were 4.3 times more likely to end up in the ICU than fully vaccinated patients and were 12.2 times more likely than fully vaccinated-plus patients. Likewise, the rate for all-cause in-hospital death for unvaccinated patients was 3.9 times greater than that for fully vaccinated patients and 15.1 times greater than that for fully vaccinated-plus patients.

The effect of vaccines emerged in waves three and four, said Dr. Frenette. “We started to see really, really significant protection and benefit from the vaccine, not only in incidence of admission but also in the incidence of complications of ICU care, ventilation, and mortality.”

Results for pediatric patients were similar to those for adults, Dr. Thampi noted. During waves five and six, overall admissions peaked, but the share of ICU admissions decreased to 9.4% from 18.1%, which was the rate during the previous four waves (OR, 0.47).

“What’s important is how pediatric hospitalizations changed over the course of the various waves,” said Dr. Thampi.

“Where we saw the highest admissions during the early Omicron dominance, we actually had the lowest numbers of hospitalizations with death and admissions into ICUs.”
 

Doing more with the data

David Fisman, MD, MPH, a professor of epidemiology at the University of Toronto, said, “This is a study that shows us how tremendously dramatic the effects of the COVID-19 vaccine were in terms of saving lives during the pandemic.” Dr. Fisman was not involved in the study.

But CNISP, which receives funding from Public Health Agency of Canada, could do more with the data it collects to better protect the public from COVID-19 and other nosocomial infections, Dr. Fisman said.

“The first problematic thing about this paper is that Canadians are paying for a surveillance system that looks at risks of acquiring infections, including COVID-19 infections, in the hospital, but that data is not fed back to the people paying for its production,” he said.

“So, Canadians don’t have the ability to really understand in real time how much risk they’re experiencing via going to the hospital for some other reason.”

The study was independently supported. Dr. Frenette and Dr. Thampi report no relevant financial relationships. Dr. Fisman has disclosed financial relationships with Pfizer, AstraZeneca, Sanofi, Seqirus, Merck, the Ontario Nurses Association, and the Elementary Teachers’ Federation of Ontario.

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

In patients with gastrointestinal (GI) malignancies, malnutrition is common. In addition, it has various negative implications, including high risk for surgical complications, prolonged hospitalization, decreased quality of life (QOL), increased mortality, and poor tolerance for treatments such as chemotherapy and radiotherapy.¹

A 2014 French study of 1903 patients hospitalized for cancer reported a 39% overall prevalence of malnutrition; 39% in patients with cancers of the colon/rectum, 60% for pancreatic cancer, and 67% for cancers of the esophagus/stomach.² Malnutrition was defined as body mass index (BMI) < 18.5 for individuals aged < 75 years or BMI < 21 for individuals aged ≥ 75 years, and/or weight loss > 10% since disease onset. Malnutrition also was strongly associated with worsened performance status.

The etiology of malnutrition in GI cancers is often multifactorial. It includes systemic tumor effects, such as inflammatory mediators contributing to hypermetabolism and cachexia, local tumor-associated mechanical obstruction, GI toxicities caused by antineoplastic therapy or other medications, and psychological factors that contribute to anorexia.³ Patient-related risk factors such as older age, other chronic diseases, and history of other GI surgeries also play a role.¹

Other studies have demonstrated that malnutrition in patients with GI malignancies undergoing surgical resection is associated with high rates of severe postoperative complications, increased length of stay (LOS) and time on a ventilator for patients treated in the intensive care unit, and poor QOL in the postoperative survival period.^4-6 Several randomized controlled trials conducted in patients with GI cancers have shown that enteral and parenteral nutrition supplementations in the perioperative period improve various outcomes, such as reduction of postoperative complication rates, fewer readmissions, improved chemotherapy tolerance, and improved QOL.^7-10 Thus, in the management of patients with GI malignancies, it is highly important to implement early nutritional screening and establish a diagnosis of malnutrition to intervene and reduce postoperative morbidity and mortality.¹

However, tools and predictors of malnutrition are often imperfect. The Academy of Nutrition and Dietetics and the American Society for Parenteral and Enteral Nutrition (AND/ASPEN) weight-based criteria define malnutrition and nutritionally-at-risk as BMI < 18.5, involuntary loss of at least 10% of body weight within 6 months or 5% within 1 month, or loss of 10 lb within 6 months.¹¹ While the ASPEN criteria are often used to define malnourishment, they may not fully capture the population at risk, and there does not exist a gold-standard tool for nutritional screening. A 2002 study that performed a critical appraisal of 44 nutritional screening tools found that no single tool was fully sufficient for application, development, evaluation, and consistent screening.¹² As such, consistently screening for malnutrition to target interventions in the perioperative period for GI surgical oncology has been challenging.¹³ More recent tools such as the perioperative nutrition screen (PONS) have been validated as rapid, effective screening tools to predict postoperative outcomes.¹⁴ Additionally, implementation of perioperative nutritional protocols, such as enhanced recovery after surgery (ERAS) in colon cancer (CC) surgery, also has shown improved perioperative care and outcomes.¹⁵

Preoperative nutritional interventions have been implemented in practice and have focused mostly on the immediate perioperative period. This has been shown to improve surgical outcomes. The Veterans Health Administration (VHA) provides comprehensive care to patients in a single-payer system, allowing for capture of perioperative data and the opportunity for focused preoperative interventions to improve outcomes.

Methods

This was a retrospective record review of colorectal malignancies treated with curative intent at the Veterans Affairs Ann Arbor Healthcare System (VAAAHS) in Michigan between January 1, 2015, and December 31, 2019. We examined nutritional status, degree of longitudinal weight loss, and subsequent clinical outcomes, including delayed postoperative recovery and delays in chemotherapy in 115 patients with CC and 33 patients with rectal cancer (RC) undergoing curative surgical resection at VAAAHS. To avoid additional confounding effects of advanced cancer, only early-stage, curable disease was included. This study was approved by the VAAAHS Institutional Review Board.

Analysis

The data were described using mean (SD) for continuous variables and number and percentages for categorical variables. Where appropriate, Fisher exact test, Pearson χ² test, Spearman ρ, and Mann-Whitney U test were used for tests of significance. SAS (SAS Institute) was utilized for multivariable analysis. The significance level was P = .05 for all tests.

Results

There were 115 patients in the CC cohort and 33 in the RC cohort. The mean (SD) age at diagnosis was 70 (9.1) for CC group and 59 (1.4) for RC group (Table 1). 

Weight Trends

From 1 year to 6 months before diagnosis, 40 of 80 patients lost weight in the CC cohort (mean change, +1.9%) and 6 of 22 patients lost weight in the RC cohort (mean change, + 0.5%). From 6 months before diagnosis to time of diagnosis, 47 of 74 patients lost weight in the CC cohort (mean change, -1.5%) and 14 of 21 patients lost weight in the RC cohort (mean change, -2.5%). From time of diagnosis to time of surgery, 36 of 104 patients with CC and 14 of 32 patients with RC lost weight with a mean weight change of and +0.1% and -0.3%, respectively. In the 6 months before surgery, any amount of weight loss was observed in 58 patients (66%) in the CC group and in 12 patients (57%) in the RC group. In this time frame, in the CC cohort, 32 patients (36%) were observed to have at least 3% weight loss, and 23 (26%) were observed to have at least 5% weight loss (Table 3). 

Nutrition Consultations

In the CC group, preoperative nutrition consultations (either inpatient or outpatient) occurred in 17 patients (15%). Inpatient postoperative nutrition evaluations occurred in 110 patients (96%) (Table 5). 

In the RC group, preoperative inpatient or outpatient nutrition consultations occurred in 12 patients (36%). Eight of those occurred before initiation of neoadjuvant chemoradiotherapy. All 33 patients received an inpatient postoperative nutrition evaluation during admission. Oral or enteral nutrition supplements were prescribed 19 times (58%). Postoperative outpatient nutrition consultations occurred for 24 patients (73%). Of the 19 patients who were readmitted to the hospital, 3 (16%) had a nutrition reconsultation on readmission.

Outcomes

The primary outcomes observed were delayed recovery, hospital readmission and LOS, and completion of adjuvant chemotherapy as indicated. Delayed recovery was observed in 35 patients with CC (40%) and 21 patients with RC (64%). Multivariable analysis in the CC cohort demonstrated that weight change was significantly associated with delayed recovery. Among those with ≥ 3% weight loss in the 6-month preoperative period (the weight measurement 6 months prior to diagnosis to date of surgery), 20 patients (63%) had delayed recovery compared with 15 patients (27%) without ≥ 3% weight loss who experienced delayed recovery (χ² = 10.84; P < .001).

Weight loss of ≥ 3% in the 6-month preoperative period also was significantly associated with complications. Of patients with at least 3% preoperative weight loss, 16 (50%) experienced complications, while 8 (14%) with < 3% preoperative weight loss experienced complications (χ² = 11.20; P < .001). Notably, ≥ 3% weight loss in the 1-year preoperative period before surgery was not significantly associated with delayed recovery. Any degree of 30-day postoperative weight loss was not correlated with delayed recovery. Finally, low preoperative albumin also was not correlated with delayed recovery (Fisher exact; P = .13). Table 3 displays differences based on presence of delayed recovery in the 88 patients with CC 6 months before surgery. Of note, ≥ 10-lb weight loss in the 6 months preceding surgery also correlated with delayed recovery (P = .01).In our cohort, 3% weight loss over 6 months had a sensitivity of 57%, specificity of 77%, positive predictive value 63%, and negative predictive value 73% for delayed recovery. By comparison, a 10-lb weight loss in 6 months per ASPEN criteria had a sensitivity of 40%, specificity of 85%, positive predictive value 64%, and negative predictive value 68% for delayed recovery.

Hospital Readmissions and LOS

Hospital readmissions occurred within the first 30 days in 11 patients (10%) in the CC cohort and 12 patients (36%) in the RC cohort. Readmissions occurred between 31 and 60 days in 4 (3%) and 7 (21%) of CC and RC cohorts, respectively. The presence of ≥ 3% weight loss in the 6-month preoperative period was significantly associated with 60-day readmissions. Among those with ≥ 3% preoperative weight loss, 8 patients (25%) had readmissions within 60 days vs 3 patients (5%) without 3% preoperative weight loss who had readmissions within 60 days (Fisher exact; P = .02).

Mean (SD) LOS was 6.4 (4.7) days (range, 1-28) for patients with CC and 8.8 (5.1) days (range, 3-23) for patients with RC. Mean (SD) LOS increased to 10.2 (4.3) days and 9.7 (6.0) days in patients with delayed recovery in the CC and RC cohorts, respectively. The mean (SD) LOS was 5.2 (2.8) days and 6.3 (2.2) days in patients without delayed recovery in the CC and RC cohorts, respectively. There was no significant difference when examining association between percent weight change and LOS for either initial admission (r_s= -0.1409; 2-tailed P = .19) or for initial and readmission combined (r_s = -0.13532; 2-tailed P = .21) within the CC cohort.

Chemotherapy

Within the CC cohort, 31 patients (27%) had an indication for adjuvant chemotherapy. Of these, 25 of 31 (81%) started chemotherapy within 12 weeks of surgical resection, and of these, 17 of 25 patients (68%) completed chemotherapy as indicated. Within the RC cohort all 33 patients had an indication for adjuvant chemotherapy, of these 18 of 33 patients (55%) began within 12 weeks of surgical resection, and 10 of 18 (56%) completed chemotherapy as indicated.

Among the CC cohort who began but did not complete adjuvant chemotherapy, there was no significant association between completion of chemotherapy and preoperative weight loss. Of patients with ≥ 3% preoperative weight loss, 3 (43%) did not complete chemotherapy vs 3 patients (27%) without preoperative weight loss who did not complete chemotherapy as indicated (Fisher exact; P = .63). Finally, low preoperative albumin did not significantly correlate with lack of completion of adjuvant chemotherapy (Fisher exact; P = .99).

Discussion

This study highlights several important findings. There were no patients in our cohort that met ASPEN malnourishment criteria with a BMI < 18.5. Twenty percent of patients lost at least 10 lb in 6 months before the operation. Notably, patients had significant associations with adverse outcomes with less pronounced weight loss than previously noted. As has been established previously, malnourishment can be difficult to screen for, and BMI also is often an imprecise tool.¹² In the CC cohort, weight loss ≥ 3% from 6 months before surgery was significantly associated with delayed recovery, complications, and hospital readmissions. We did not identify a statistically significant effect on chemotherapy completion. However, the numerical difference was suggestive of a difference, and a type 2 error is possible due to our limited sample size.

Our findings imply that the effects of even mild malnutrition are even more profound than previously thought. Significantly, this applies to overweight and obese patients as well, as these constituted a significant fraction of our cohort. A finding of ≥ 3% weight loss at the time of CC diagnosis may provide an opportunity for a focused nutrition intervention up to the time of surgery. Second, although nutrition consultation was frequent in the inpatient setting during the hospital admission (96%-100%), rates of nutrition evaluation were as low as 15% before surgery and 12% after surgery, representing a key area for improvement and focused intervention. An optimal time for intervention and nutrition prehabilitation would be at time of diagnosis before surgery with plans for continued aggressive monitoring and subsequent follow-up. Our finding seems to provide a more sensitive tool to identify patients at risk for delayed recovery compared with the ASPEN-driven assessment. Given the simplicity and the clinical significance, our test consisting of 3% weight loss over 6 months, with its sensitivity of 57%, may be superior to the ASPEN 10-lb weight loss, with its sensitivity of 40% in our cohort.

Previous Studies

Our findings are consistent with previous studies that have demonstrated that perioperative weight loss and malnutrition are correlated with delayed recovery and complications, such as wound healing, in patients with GI cancer.^2,4,5,8 In a retrospective study of more than 7000 patients with CC, those who were overweight or obese were found to have an improved overall survival compared with other BMI categories, and those who were underweight had an increased 30-day mortality and postoperative complications.¹⁶

In another retrospective study of 3799 patients with CC, those who were overweight and obese had an improved 5-year survival rate compared with patients whose weight was normal or underweight. Outcomes were found to be stage dependent.¹⁷ In this study cohort, all patients were either overweight or obese and remained in that category even with weight loss. This may have contributed to overall improved outcomes.

Implications and Next Steps

Our study has several implications. One is that BMI criteria < 18.5 may not be a good measure for malnutrition given that about 75% of the patients in our cohort were overweight or obese and none were underweight. We also show a concrete, easily identifiable finding of percent weight change that could be addressed as an automated electronic notification and potentially identify a patient at risk and serve as a trigger for both timely and early nutrition intervention. It seems to be more sensitive than the ASPEN criterion of 10-lb weight loss in 6 months before surgery. Sensitivity is especially appealing given the ease and potential of embedding this tool in an electronic health record and the clinical importance of the consequent intervention. Preoperative as opposed to perioperative nutrition optimization at time of CC diagnosis is essential, as it may help improve postsurgical outcomes as well as oncologic outcomes, including completion of adjuvant chemotherapy. Finally, although our study found that rates of inpatient postoperative nutrition consultation were high, rates of outpatient nutrition consultation in the preoperative period were low. This represents a missed opportunity for intervention before surgery. Similarly, rates of postoperative nutrition follow-up period were low, which points to an area for improvement in longitudinal and holistic care.

We suggest modifications to nutrition intervention protocols, such as ERAS, which should start at the time of GI malignancy diagnosis.¹⁸ Other suggestions include standard involvement of nutritionists in inpatient and outpatient settings with longitudinal follow-up in the preoperative and postoperative periods and patient enrollment in a nutrition program with monitoring at time of diagnosis at the VHA. Our findings as well as previous literature suggest that the preoperative period is the most important time to intervene with regard to nutrition optimization and represents an opportunity for intensive prehabilitation. Future areas of research include incorporating other important measures of malnourishment independent of BMI into future study designs, such as sarcopenia and adipose tissue density, to better assess body composition and predict prognostic risk in CC.^18,19

Strengths and Limitations

This study is limited by its single-center, retrospective design and small sample sizes, and we acknowledge the limitations of our data set. However, the strength of this VHA-based study is that the single-payer system allows for complete capture of perioperative data as well as the opportunity for focused preoperative interventions to improve outcomes. To our knowledge, there is no currently existing literature on improving nutrition protocols at the VHA for patients with a GI malignancy. These retrospective data will help inform current gaps in quality improvement and supportive oncology as it relates to optimizing malnourishment in veterans undergoing surgical resection for their cancer.

Conclusions

In the CC cohort, weight loss of ≥ 3% from 6 months prior to time of surgery was significantly associated with delayed recovery, complications, and hospital readmissions. Our findings suggest that patients with CC undergoing surgery may benefit from an intensive, early nutrition prehabilitation. Preoperative nutrition optimization may help improve postsurgical outcomes as well as oncologic outcomes, including completion of adjuvant chemotherapy. Further research would be able to clarify these hypotheses.

In patients with gastrointestinal (GI) malignancies, malnutrition is common. In addition, it has various negative implications, including high risk for surgical complications, prolonged hospitalization, decreased quality of life (QOL), increased mortality, and poor tolerance for treatments such as chemotherapy and radiotherapy.¹

A 2014 French study of 1903 patients hospitalized for cancer reported a 39% overall prevalence of malnutrition; 39% in patients with cancers of the colon/rectum, 60% for pancreatic cancer, and 67% for cancers of the esophagus/stomach.² Malnutrition was defined as body mass index (BMI) < 18.5 for individuals aged < 75 years or BMI < 21 for individuals aged ≥ 75 years, and/or weight loss > 10% since disease onset. Malnutrition also was strongly associated with worsened performance status.

The etiology of malnutrition in GI cancers is often multifactorial. It includes systemic tumor effects, such as inflammatory mediators contributing to hypermetabolism and cachexia, local tumor-associated mechanical obstruction, GI toxicities caused by antineoplastic therapy or other medications, and psychological factors that contribute to anorexia.³ Patient-related risk factors such as older age, other chronic diseases, and history of other GI surgeries also play a role.¹

Other studies have demonstrated that malnutrition in patients with GI malignancies undergoing surgical resection is associated with high rates of severe postoperative complications, increased length of stay (LOS) and time on a ventilator for patients treated in the intensive care unit, and poor QOL in the postoperative survival period.^4-6 Several randomized controlled trials conducted in patients with GI cancers have shown that enteral and parenteral nutrition supplementations in the perioperative period improve various outcomes, such as reduction of postoperative complication rates, fewer readmissions, improved chemotherapy tolerance, and improved QOL.^7-10 Thus, in the management of patients with GI malignancies, it is highly important to implement early nutritional screening and establish a diagnosis of malnutrition to intervene and reduce postoperative morbidity and mortality.¹

However, tools and predictors of malnutrition are often imperfect. The Academy of Nutrition and Dietetics and the American Society for Parenteral and Enteral Nutrition (AND/ASPEN) weight-based criteria define malnutrition and nutritionally-at-risk as BMI < 18.5, involuntary loss of at least 10% of body weight within 6 months or 5% within 1 month, or loss of 10 lb within 6 months.¹¹ While the ASPEN criteria are often used to define malnourishment, they may not fully capture the population at risk, and there does not exist a gold-standard tool for nutritional screening. A 2002 study that performed a critical appraisal of 44 nutritional screening tools found that no single tool was fully sufficient for application, development, evaluation, and consistent screening.¹² As such, consistently screening for malnutrition to target interventions in the perioperative period for GI surgical oncology has been challenging.¹³ More recent tools such as the perioperative nutrition screen (PONS) have been validated as rapid, effective screening tools to predict postoperative outcomes.¹⁴ Additionally, implementation of perioperative nutritional protocols, such as enhanced recovery after surgery (ERAS) in colon cancer (CC) surgery, also has shown improved perioperative care and outcomes.¹⁵

Preoperative nutritional interventions have been implemented in practice and have focused mostly on the immediate perioperative period. This has been shown to improve surgical outcomes. The Veterans Health Administration (VHA) provides comprehensive care to patients in a single-payer system, allowing for capture of perioperative data and the opportunity for focused preoperative interventions to improve outcomes.

Methods

This was a retrospective record review of colorectal malignancies treated with curative intent at the Veterans Affairs Ann Arbor Healthcare System (VAAAHS) in Michigan between January 1, 2015, and December 31, 2019. We examined nutritional status, degree of longitudinal weight loss, and subsequent clinical outcomes, including delayed postoperative recovery and delays in chemotherapy in 115 patients with CC and 33 patients with rectal cancer (RC) undergoing curative surgical resection at VAAAHS. To avoid additional confounding effects of advanced cancer, only early-stage, curable disease was included. This study was approved by the VAAAHS Institutional Review Board.

Analysis

The data were described using mean (SD) for continuous variables and number and percentages for categorical variables. Where appropriate, Fisher exact test, Pearson χ² test, Spearman ρ, and Mann-Whitney U test were used for tests of significance. SAS (SAS Institute) was utilized for multivariable analysis. The significance level was P = .05 for all tests.

Results

There were 115 patients in the CC cohort and 33 in the RC cohort. The mean (SD) age at diagnosis was 70 (9.1) for CC group and 59 (1.4) for RC group (Table 1). 

Weight Trends

From 1 year to 6 months before diagnosis, 40 of 80 patients lost weight in the CC cohort (mean change, +1.9%) and 6 of 22 patients lost weight in the RC cohort (mean change, + 0.5%). From 6 months before diagnosis to time of diagnosis, 47 of 74 patients lost weight in the CC cohort (mean change, -1.5%) and 14 of 21 patients lost weight in the RC cohort (mean change, -2.5%). From time of diagnosis to time of surgery, 36 of 104 patients with CC and 14 of 32 patients with RC lost weight with a mean weight change of and +0.1% and -0.3%, respectively. In the 6 months before surgery, any amount of weight loss was observed in 58 patients (66%) in the CC group and in 12 patients (57%) in the RC group. In this time frame, in the CC cohort, 32 patients (36%) were observed to have at least 3% weight loss, and 23 (26%) were observed to have at least 5% weight loss (Table 3). 

Nutrition Consultations

In the CC group, preoperative nutrition consultations (either inpatient or outpatient) occurred in 17 patients (15%). Inpatient postoperative nutrition evaluations occurred in 110 patients (96%) (Table 5). 

In the RC group, preoperative inpatient or outpatient nutrition consultations occurred in 12 patients (36%). Eight of those occurred before initiation of neoadjuvant chemoradiotherapy. All 33 patients received an inpatient postoperative nutrition evaluation during admission. Oral or enteral nutrition supplements were prescribed 19 times (58%). Postoperative outpatient nutrition consultations occurred for 24 patients (73%). Of the 19 patients who were readmitted to the hospital, 3 (16%) had a nutrition reconsultation on readmission.

Outcomes

The primary outcomes observed were delayed recovery, hospital readmission and LOS, and completion of adjuvant chemotherapy as indicated. Delayed recovery was observed in 35 patients with CC (40%) and 21 patients with RC (64%). Multivariable analysis in the CC cohort demonstrated that weight change was significantly associated with delayed recovery. Among those with ≥ 3% weight loss in the 6-month preoperative period (the weight measurement 6 months prior to diagnosis to date of surgery), 20 patients (63%) had delayed recovery compared with 15 patients (27%) without ≥ 3% weight loss who experienced delayed recovery (χ² = 10.84; P < .001).

Weight loss of ≥ 3% in the 6-month preoperative period also was significantly associated with complications. Of patients with at least 3% preoperative weight loss, 16 (50%) experienced complications, while 8 (14%) with < 3% preoperative weight loss experienced complications (χ² = 11.20; P < .001). Notably, ≥ 3% weight loss in the 1-year preoperative period before surgery was not significantly associated with delayed recovery. Any degree of 30-day postoperative weight loss was not correlated with delayed recovery. Finally, low preoperative albumin also was not correlated with delayed recovery (Fisher exact; P = .13). Table 3 displays differences based on presence of delayed recovery in the 88 patients with CC 6 months before surgery. Of note, ≥ 10-lb weight loss in the 6 months preceding surgery also correlated with delayed recovery (P = .01).In our cohort, 3% weight loss over 6 months had a sensitivity of 57%, specificity of 77%, positive predictive value 63%, and negative predictive value 73% for delayed recovery. By comparison, a 10-lb weight loss in 6 months per ASPEN criteria had a sensitivity of 40%, specificity of 85%, positive predictive value 64%, and negative predictive value 68% for delayed recovery.

Hospital Readmissions and LOS

Hospital readmissions occurred within the first 30 days in 11 patients (10%) in the CC cohort and 12 patients (36%) in the RC cohort. Readmissions occurred between 31 and 60 days in 4 (3%) and 7 (21%) of CC and RC cohorts, respectively. The presence of ≥ 3% weight loss in the 6-month preoperative period was significantly associated with 60-day readmissions. Among those with ≥ 3% preoperative weight loss, 8 patients (25%) had readmissions within 60 days vs 3 patients (5%) without 3% preoperative weight loss who had readmissions within 60 days (Fisher exact; P = .02).

Mean (SD) LOS was 6.4 (4.7) days (range, 1-28) for patients with CC and 8.8 (5.1) days (range, 3-23) for patients with RC. Mean (SD) LOS increased to 10.2 (4.3) days and 9.7 (6.0) days in patients with delayed recovery in the CC and RC cohorts, respectively. The mean (SD) LOS was 5.2 (2.8) days and 6.3 (2.2) days in patients without delayed recovery in the CC and RC cohorts, respectively. There was no significant difference when examining association between percent weight change and LOS for either initial admission (r_s= -0.1409; 2-tailed P = .19) or for initial and readmission combined (r_s = -0.13532; 2-tailed P = .21) within the CC cohort.

Chemotherapy

Within the CC cohort, 31 patients (27%) had an indication for adjuvant chemotherapy. Of these, 25 of 31 (81%) started chemotherapy within 12 weeks of surgical resection, and of these, 17 of 25 patients (68%) completed chemotherapy as indicated. Within the RC cohort all 33 patients had an indication for adjuvant chemotherapy, of these 18 of 33 patients (55%) began within 12 weeks of surgical resection, and 10 of 18 (56%) completed chemotherapy as indicated.

Among the CC cohort who began but did not complete adjuvant chemotherapy, there was no significant association between completion of chemotherapy and preoperative weight loss. Of patients with ≥ 3% preoperative weight loss, 3 (43%) did not complete chemotherapy vs 3 patients (27%) without preoperative weight loss who did not complete chemotherapy as indicated (Fisher exact; P = .63). Finally, low preoperative albumin did not significantly correlate with lack of completion of adjuvant chemotherapy (Fisher exact; P = .99).

Discussion

This study highlights several important findings. There were no patients in our cohort that met ASPEN malnourishment criteria with a BMI < 18.5. Twenty percent of patients lost at least 10 lb in 6 months before the operation. Notably, patients had significant associations with adverse outcomes with less pronounced weight loss than previously noted. As has been established previously, malnourishment can be difficult to screen for, and BMI also is often an imprecise tool.¹² In the CC cohort, weight loss ≥ 3% from 6 months before surgery was significantly associated with delayed recovery, complications, and hospital readmissions. We did not identify a statistically significant effect on chemotherapy completion. However, the numerical difference was suggestive of a difference, and a type 2 error is possible due to our limited sample size.

Our findings imply that the effects of even mild malnutrition are even more profound than previously thought. Significantly, this applies to overweight and obese patients as well, as these constituted a significant fraction of our cohort. A finding of ≥ 3% weight loss at the time of CC diagnosis may provide an opportunity for a focused nutrition intervention up to the time of surgery. Second, although nutrition consultation was frequent in the inpatient setting during the hospital admission (96%-100%), rates of nutrition evaluation were as low as 15% before surgery and 12% after surgery, representing a key area for improvement and focused intervention. An optimal time for intervention and nutrition prehabilitation would be at time of diagnosis before surgery with plans for continued aggressive monitoring and subsequent follow-up. Our finding seems to provide a more sensitive tool to identify patients at risk for delayed recovery compared with the ASPEN-driven assessment. Given the simplicity and the clinical significance, our test consisting of 3% weight loss over 6 months, with its sensitivity of 57%, may be superior to the ASPEN 10-lb weight loss, with its sensitivity of 40% in our cohort.

Previous Studies

Our findings are consistent with previous studies that have demonstrated that perioperative weight loss and malnutrition are correlated with delayed recovery and complications, such as wound healing, in patients with GI cancer.^2,4,5,8 In a retrospective study of more than 7000 patients with CC, those who were overweight or obese were found to have an improved overall survival compared with other BMI categories, and those who were underweight had an increased 30-day mortality and postoperative complications.¹⁶

In another retrospective study of 3799 patients with CC, those who were overweight and obese had an improved 5-year survival rate compared with patients whose weight was normal or underweight. Outcomes were found to be stage dependent.¹⁷ In this study cohort, all patients were either overweight or obese and remained in that category even with weight loss. This may have contributed to overall improved outcomes.

Implications and Next Steps

Our study has several implications. One is that BMI criteria < 18.5 may not be a good measure for malnutrition given that about 75% of the patients in our cohort were overweight or obese and none were underweight. We also show a concrete, easily identifiable finding of percent weight change that could be addressed as an automated electronic notification and potentially identify a patient at risk and serve as a trigger for both timely and early nutrition intervention. It seems to be more sensitive than the ASPEN criterion of 10-lb weight loss in 6 months before surgery. Sensitivity is especially appealing given the ease and potential of embedding this tool in an electronic health record and the clinical importance of the consequent intervention. Preoperative as opposed to perioperative nutrition optimization at time of CC diagnosis is essential, as it may help improve postsurgical outcomes as well as oncologic outcomes, including completion of adjuvant chemotherapy. Finally, although our study found that rates of inpatient postoperative nutrition consultation were high, rates of outpatient nutrition consultation in the preoperative period were low. This represents a missed opportunity for intervention before surgery. Similarly, rates of postoperative nutrition follow-up period were low, which points to an area for improvement in longitudinal and holistic care.

We suggest modifications to nutrition intervention protocols, such as ERAS, which should start at the time of GI malignancy diagnosis.¹⁸ Other suggestions include standard involvement of nutritionists in inpatient and outpatient settings with longitudinal follow-up in the preoperative and postoperative periods and patient enrollment in a nutrition program with monitoring at time of diagnosis at the VHA. Our findings as well as previous literature suggest that the preoperative period is the most important time to intervene with regard to nutrition optimization and represents an opportunity for intensive prehabilitation. Future areas of research include incorporating other important measures of malnourishment independent of BMI into future study designs, such as sarcopenia and adipose tissue density, to better assess body composition and predict prognostic risk in CC.^18,19

Strengths and Limitations

This study is limited by its single-center, retrospective design and small sample sizes, and we acknowledge the limitations of our data set. However, the strength of this VHA-based study is that the single-payer system allows for complete capture of perioperative data as well as the opportunity for focused preoperative interventions to improve outcomes. To our knowledge, there is no currently existing literature on improving nutrition protocols at the VHA for patients with a GI malignancy. These retrospective data will help inform current gaps in quality improvement and supportive oncology as it relates to optimizing malnourishment in veterans undergoing surgical resection for their cancer.

Conclusions

In the CC cohort, weight loss of ≥ 3% from 6 months prior to time of surgery was significantly associated with delayed recovery, complications, and hospital readmissions. Our findings suggest that patients with CC undergoing surgery may benefit from an intensive, early nutrition prehabilitation. Preoperative nutrition optimization may help improve postsurgical outcomes as well as oncologic outcomes, including completion of adjuvant chemotherapy. Further research would be able to clarify these hypotheses.

In patients with gastrointestinal (GI) malignancies, malnutrition is common. In addition, it has various negative implications, including high risk for surgical complications, prolonged hospitalization, decreased quality of life (QOL), increased mortality, and poor tolerance for treatments such as chemotherapy and radiotherapy.¹

A 2014 French study of 1903 patients hospitalized for cancer reported a 39% overall prevalence of malnutrition; 39% in patients with cancers of the colon/rectum, 60% for pancreatic cancer, and 67% for cancers of the esophagus/stomach.² Malnutrition was defined as body mass index (BMI) < 18.5 for individuals aged < 75 years or BMI < 21 for individuals aged ≥ 75 years, and/or weight loss > 10% since disease onset. Malnutrition also was strongly associated with worsened performance status.

The etiology of malnutrition in GI cancers is often multifactorial. It includes systemic tumor effects, such as inflammatory mediators contributing to hypermetabolism and cachexia, local tumor-associated mechanical obstruction, GI toxicities caused by antineoplastic therapy or other medications, and psychological factors that contribute to anorexia.³ Patient-related risk factors such as older age, other chronic diseases, and history of other GI surgeries also play a role.¹

Other studies have demonstrated that malnutrition in patients with GI malignancies undergoing surgical resection is associated with high rates of severe postoperative complications, increased length of stay (LOS) and time on a ventilator for patients treated in the intensive care unit, and poor QOL in the postoperative survival period.^4-6 Several randomized controlled trials conducted in patients with GI cancers have shown that enteral and parenteral nutrition supplementations in the perioperative period improve various outcomes, such as reduction of postoperative complication rates, fewer readmissions, improved chemotherapy tolerance, and improved QOL.^7-10 Thus, in the management of patients with GI malignancies, it is highly important to implement early nutritional screening and establish a diagnosis of malnutrition to intervene and reduce postoperative morbidity and mortality.¹

However, tools and predictors of malnutrition are often imperfect. The Academy of Nutrition and Dietetics and the American Society for Parenteral and Enteral Nutrition (AND/ASPEN) weight-based criteria define malnutrition and nutritionally-at-risk as BMI < 18.5, involuntary loss of at least 10% of body weight within 6 months or 5% within 1 month, or loss of 10 lb within 6 months.¹¹ While the ASPEN criteria are often used to define malnourishment, they may not fully capture the population at risk, and there does not exist a gold-standard tool for nutritional screening. A 2002 study that performed a critical appraisal of 44 nutritional screening tools found that no single tool was fully sufficient for application, development, evaluation, and consistent screening.¹² As such, consistently screening for malnutrition to target interventions in the perioperative period for GI surgical oncology has been challenging.¹³ More recent tools such as the perioperative nutrition screen (PONS) have been validated as rapid, effective screening tools to predict postoperative outcomes.¹⁴ Additionally, implementation of perioperative nutritional protocols, such as enhanced recovery after surgery (ERAS) in colon cancer (CC) surgery, also has shown improved perioperative care and outcomes.¹⁵

Preoperative nutritional interventions have been implemented in practice and have focused mostly on the immediate perioperative period. This has been shown to improve surgical outcomes. The Veterans Health Administration (VHA) provides comprehensive care to patients in a single-payer system, allowing for capture of perioperative data and the opportunity for focused preoperative interventions to improve outcomes.

Methods

This was a retrospective record review of colorectal malignancies treated with curative intent at the Veterans Affairs Ann Arbor Healthcare System (VAAAHS) in Michigan between January 1, 2015, and December 31, 2019. We examined nutritional status, degree of longitudinal weight loss, and subsequent clinical outcomes, including delayed postoperative recovery and delays in chemotherapy in 115 patients with CC and 33 patients with rectal cancer (RC) undergoing curative surgical resection at VAAAHS. To avoid additional confounding effects of advanced cancer, only early-stage, curable disease was included. This study was approved by the VAAAHS Institutional Review Board.

Analysis

The data were described using mean (SD) for continuous variables and number and percentages for categorical variables. Where appropriate, Fisher exact test, Pearson χ² test, Spearman ρ, and Mann-Whitney U test were used for tests of significance. SAS (SAS Institute) was utilized for multivariable analysis. The significance level was P = .05 for all tests.

Results

There were 115 patients in the CC cohort and 33 in the RC cohort. The mean (SD) age at diagnosis was 70 (9.1) for CC group and 59 (1.4) for RC group (Table 1). 

Weight Trends

From 1 year to 6 months before diagnosis, 40 of 80 patients lost weight in the CC cohort (mean change, +1.9%) and 6 of 22 patients lost weight in the RC cohort (mean change, + 0.5%). From 6 months before diagnosis to time of diagnosis, 47 of 74 patients lost weight in the CC cohort (mean change, -1.5%) and 14 of 21 patients lost weight in the RC cohort (mean change, -2.5%). From time of diagnosis to time of surgery, 36 of 104 patients with CC and 14 of 32 patients with RC lost weight with a mean weight change of and +0.1% and -0.3%, respectively. In the 6 months before surgery, any amount of weight loss was observed in 58 patients (66%) in the CC group and in 12 patients (57%) in the RC group. In this time frame, in the CC cohort, 32 patients (36%) were observed to have at least 3% weight loss, and 23 (26%) were observed to have at least 5% weight loss (Table 3). 

Nutrition Consultations

In the CC group, preoperative nutrition consultations (either inpatient or outpatient) occurred in 17 patients (15%). Inpatient postoperative nutrition evaluations occurred in 110 patients (96%) (Table 5). 

In the RC group, preoperative inpatient or outpatient nutrition consultations occurred in 12 patients (36%). Eight of those occurred before initiation of neoadjuvant chemoradiotherapy. All 33 patients received an inpatient postoperative nutrition evaluation during admission. Oral or enteral nutrition supplements were prescribed 19 times (58%). Postoperative outpatient nutrition consultations occurred for 24 patients (73%). Of the 19 patients who were readmitted to the hospital, 3 (16%) had a nutrition reconsultation on readmission.

Outcomes

The primary outcomes observed were delayed recovery, hospital readmission and LOS, and completion of adjuvant chemotherapy as indicated. Delayed recovery was observed in 35 patients with CC (40%) and 21 patients with RC (64%). Multivariable analysis in the CC cohort demonstrated that weight change was significantly associated with delayed recovery. Among those with ≥ 3% weight loss in the 6-month preoperative period (the weight measurement 6 months prior to diagnosis to date of surgery), 20 patients (63%) had delayed recovery compared with 15 patients (27%) without ≥ 3% weight loss who experienced delayed recovery (χ² = 10.84; P < .001).

Weight loss of ≥ 3% in the 6-month preoperative period also was significantly associated with complications. Of patients with at least 3% preoperative weight loss, 16 (50%) experienced complications, while 8 (14%) with < 3% preoperative weight loss experienced complications (χ² = 11.20; P < .001). Notably, ≥ 3% weight loss in the 1-year preoperative period before surgery was not significantly associated with delayed recovery. Any degree of 30-day postoperative weight loss was not correlated with delayed recovery. Finally, low preoperative albumin also was not correlated with delayed recovery (Fisher exact; P = .13). Table 3 displays differences based on presence of delayed recovery in the 88 patients with CC 6 months before surgery. Of note, ≥ 10-lb weight loss in the 6 months preceding surgery also correlated with delayed recovery (P = .01).In our cohort, 3% weight loss over 6 months had a sensitivity of 57%, specificity of 77%, positive predictive value 63%, and negative predictive value 73% for delayed recovery. By comparison, a 10-lb weight loss in 6 months per ASPEN criteria had a sensitivity of 40%, specificity of 85%, positive predictive value 64%, and negative predictive value 68% for delayed recovery.

Hospital Readmissions and LOS

Hospital readmissions occurred within the first 30 days in 11 patients (10%) in the CC cohort and 12 patients (36%) in the RC cohort. Readmissions occurred between 31 and 60 days in 4 (3%) and 7 (21%) of CC and RC cohorts, respectively. The presence of ≥ 3% weight loss in the 6-month preoperative period was significantly associated with 60-day readmissions. Among those with ≥ 3% preoperative weight loss, 8 patients (25%) had readmissions within 60 days vs 3 patients (5%) without 3% preoperative weight loss who had readmissions within 60 days (Fisher exact; P = .02).

Mean (SD) LOS was 6.4 (4.7) days (range, 1-28) for patients with CC and 8.8 (5.1) days (range, 3-23) for patients with RC. Mean (SD) LOS increased to 10.2 (4.3) days and 9.7 (6.0) days in patients with delayed recovery in the CC and RC cohorts, respectively. The mean (SD) LOS was 5.2 (2.8) days and 6.3 (2.2) days in patients without delayed recovery in the CC and RC cohorts, respectively. There was no significant difference when examining association between percent weight change and LOS for either initial admission (r_s= -0.1409; 2-tailed P = .19) or for initial and readmission combined (r_s = -0.13532; 2-tailed P = .21) within the CC cohort.

Chemotherapy

Within the CC cohort, 31 patients (27%) had an indication for adjuvant chemotherapy. Of these, 25 of 31 (81%) started chemotherapy within 12 weeks of surgical resection, and of these, 17 of 25 patients (68%) completed chemotherapy as indicated. Within the RC cohort all 33 patients had an indication for adjuvant chemotherapy, of these 18 of 33 patients (55%) began within 12 weeks of surgical resection, and 10 of 18 (56%) completed chemotherapy as indicated.

Among the CC cohort who began but did not complete adjuvant chemotherapy, there was no significant association between completion of chemotherapy and preoperative weight loss. Of patients with ≥ 3% preoperative weight loss, 3 (43%) did not complete chemotherapy vs 3 patients (27%) without preoperative weight loss who did not complete chemotherapy as indicated (Fisher exact; P = .63). Finally, low preoperative albumin did not significantly correlate with lack of completion of adjuvant chemotherapy (Fisher exact; P = .99).

Discussion

This study highlights several important findings. There were no patients in our cohort that met ASPEN malnourishment criteria with a BMI < 18.5. Twenty percent of patients lost at least 10 lb in 6 months before the operation. Notably, patients had significant associations with adverse outcomes with less pronounced weight loss than previously noted. As has been established previously, malnourishment can be difficult to screen for, and BMI also is often an imprecise tool.¹² In the CC cohort, weight loss ≥ 3% from 6 months before surgery was significantly associated with delayed recovery, complications, and hospital readmissions. We did not identify a statistically significant effect on chemotherapy completion. However, the numerical difference was suggestive of a difference, and a type 2 error is possible due to our limited sample size.

Our findings imply that the effects of even mild malnutrition are even more profound than previously thought. Significantly, this applies to overweight and obese patients as well, as these constituted a significant fraction of our cohort. A finding of ≥ 3% weight loss at the time of CC diagnosis may provide an opportunity for a focused nutrition intervention up to the time of surgery. Second, although nutrition consultation was frequent in the inpatient setting during the hospital admission (96%-100%), rates of nutrition evaluation were as low as 15% before surgery and 12% after surgery, representing a key area for improvement and focused intervention. An optimal time for intervention and nutrition prehabilitation would be at time of diagnosis before surgery with plans for continued aggressive monitoring and subsequent follow-up. Our finding seems to provide a more sensitive tool to identify patients at risk for delayed recovery compared with the ASPEN-driven assessment. Given the simplicity and the clinical significance, our test consisting of 3% weight loss over 6 months, with its sensitivity of 57%, may be superior to the ASPEN 10-lb weight loss, with its sensitivity of 40% in our cohort.

Previous Studies

Our findings are consistent with previous studies that have demonstrated that perioperative weight loss and malnutrition are correlated with delayed recovery and complications, such as wound healing, in patients with GI cancer.^2,4,5,8 In a retrospective study of more than 7000 patients with CC, those who were overweight or obese were found to have an improved overall survival compared with other BMI categories, and those who were underweight had an increased 30-day mortality and postoperative complications.¹⁶

In another retrospective study of 3799 patients with CC, those who were overweight and obese had an improved 5-year survival rate compared with patients whose weight was normal or underweight. Outcomes were found to be stage dependent.¹⁷ In this study cohort, all patients were either overweight or obese and remained in that category even with weight loss. This may have contributed to overall improved outcomes.

Implications and Next Steps

Our study has several implications. One is that BMI criteria < 18.5 may not be a good measure for malnutrition given that about 75% of the patients in our cohort were overweight or obese and none were underweight. We also show a concrete, easily identifiable finding of percent weight change that could be addressed as an automated electronic notification and potentially identify a patient at risk and serve as a trigger for both timely and early nutrition intervention. It seems to be more sensitive than the ASPEN criterion of 10-lb weight loss in 6 months before surgery. Sensitivity is especially appealing given the ease and potential of embedding this tool in an electronic health record and the clinical importance of the consequent intervention. Preoperative as opposed to perioperative nutrition optimization at time of CC diagnosis is essential, as it may help improve postsurgical outcomes as well as oncologic outcomes, including completion of adjuvant chemotherapy. Finally, although our study found that rates of inpatient postoperative nutrition consultation were high, rates of outpatient nutrition consultation in the preoperative period were low. This represents a missed opportunity for intervention before surgery. Similarly, rates of postoperative nutrition follow-up period were low, which points to an area for improvement in longitudinal and holistic care.

We suggest modifications to nutrition intervention protocols, such as ERAS, which should start at the time of GI malignancy diagnosis.¹⁸ Other suggestions include standard involvement of nutritionists in inpatient and outpatient settings with longitudinal follow-up in the preoperative and postoperative periods and patient enrollment in a nutrition program with monitoring at time of diagnosis at the VHA. Our findings as well as previous literature suggest that the preoperative period is the most important time to intervene with regard to nutrition optimization and represents an opportunity for intensive prehabilitation. Future areas of research include incorporating other important measures of malnourishment independent of BMI into future study designs, such as sarcopenia and adipose tissue density, to better assess body composition and predict prognostic risk in CC.^18,19

Strengths and Limitations

This study is limited by its single-center, retrospective design and small sample sizes, and we acknowledge the limitations of our data set. However, the strength of this VHA-based study is that the single-payer system allows for complete capture of perioperative data as well as the opportunity for focused preoperative interventions to improve outcomes. To our knowledge, there is no currently existing literature on improving nutrition protocols at the VHA for patients with a GI malignancy. These retrospective data will help inform current gaps in quality improvement and supportive oncology as it relates to optimizing malnourishment in veterans undergoing surgical resection for their cancer.

Conclusions

In the CC cohort, weight loss of ≥ 3% from 6 months prior to time of surgery was significantly associated with delayed recovery, complications, and hospital readmissions. Our findings suggest that patients with CC undergoing surgery may benefit from an intensive, early nutrition prehabilitation. Preoperative nutrition optimization may help improve postsurgical outcomes as well as oncologic outcomes, including completion of adjuvant chemotherapy. Further research would be able to clarify these hypotheses.

Sleep Medicine Network

Respiratory-related Sleep Disorders Section

Home sleep apnea test: Peripheral arterial tonometry

OSA is associated with serious health consequences and increased health care utilization (Kapur V, et al. Sleep. 1999:22[6]:749).

Polysomnography (PSG) is the gold standard for diagnosis, but is expensive, cumbersome, and inconsistently accessible. Home sleep apnea test (HSAT) devices provide a cost effective, convenient method to diagnose OSA and are non-inferior to PSG when considering treatment outcomes in uncomplicated adults with suggestive symptoms (Kapur VK, et al. J Clin Sleep Med. 2017;13[3]:479; Skomro RP, et al. Chest. 2010;138[2]:257).

Utilization of HSAT devices has increased in recent years, partly due to the COVID-19 pandemic and limitations in insurance reimbursement for PSG as the initial diagnostic test. But while there are benefits to home testing with respect to convenience and increased access, we must take the clinical context into account.

Peripheral arterial tonometry (PAT) is a commonly used HSAT technology, which measures peripheral arterial vascular tone using plethysmography at the fingertip. It has a sensitivity of 80% and specificity of 83% for detecting OSA in patients without significant comorbidities and high pretest probability of OSA compared to PSG (Ward KL, et al. J Clin Sleep Med. 2015;11[4]:433). But PAT has also been criticized for lacking diagnostic accuracy, particularly when including patients with mild OSA in analysis (Ichikawa M, et al. J Sleep Res. 2022;31[6]:e13682).

HSAT devices using PAT technology have been studied in patients with atrial fibrillation (Tauman R, et al. Nat Sci Sleep. 2020;12:1115), adolescents (Choi JH, et al. J Clin Sleep Med. 2018;14[10]:1741), and pregnant women (O’Brien LM, et al. J Clin Sleep Med. 2012;8[3]:287), and to assess OSA treatment adequacy with varying sensitivity and specificity. Study in special populations may allow for increased access to testing with the benefit of increased recognition of a generally underdiagnosed disorder. But it’s important to use HSAT alongside awareness of its limitations and it should not replace good clinical judgment when making treatment decisions.

Dimple Tejwani, MD

Member-at-Large

Kara Dupuy-McCauley, MD

Member-at-Large

Sleep Medicine Network

Respiratory-related Sleep Disorders Section

Home sleep apnea test: Peripheral arterial tonometry

OSA is associated with serious health consequences and increased health care utilization (Kapur V, et al. Sleep. 1999:22[6]:749).

Polysomnography (PSG) is the gold standard for diagnosis, but is expensive, cumbersome, and inconsistently accessible. Home sleep apnea test (HSAT) devices provide a cost effective, convenient method to diagnose OSA and are non-inferior to PSG when considering treatment outcomes in uncomplicated adults with suggestive symptoms (Kapur VK, et al. J Clin Sleep Med. 2017;13[3]:479; Skomro RP, et al. Chest. 2010;138[2]:257).

Utilization of HSAT devices has increased in recent years, partly due to the COVID-19 pandemic and limitations in insurance reimbursement for PSG as the initial diagnostic test. But while there are benefits to home testing with respect to convenience and increased access, we must take the clinical context into account.

Peripheral arterial tonometry (PAT) is a commonly used HSAT technology, which measures peripheral arterial vascular tone using plethysmography at the fingertip. It has a sensitivity of 80% and specificity of 83% for detecting OSA in patients without significant comorbidities and high pretest probability of OSA compared to PSG (Ward KL, et al. J Clin Sleep Med. 2015;11[4]:433). But PAT has also been criticized for lacking diagnostic accuracy, particularly when including patients with mild OSA in analysis (Ichikawa M, et al. J Sleep Res. 2022;31[6]:e13682).

HSAT devices using PAT technology have been studied in patients with atrial fibrillation (Tauman R, et al. Nat Sci Sleep. 2020;12:1115), adolescents (Choi JH, et al. J Clin Sleep Med. 2018;14[10]:1741), and pregnant women (O’Brien LM, et al. J Clin Sleep Med. 2012;8[3]:287), and to assess OSA treatment adequacy with varying sensitivity and specificity. Study in special populations may allow for increased access to testing with the benefit of increased recognition of a generally underdiagnosed disorder. But it’s important to use HSAT alongside awareness of its limitations and it should not replace good clinical judgment when making treatment decisions.

Dimple Tejwani, MD

Member-at-Large

Kara Dupuy-McCauley, MD

Member-at-Large

Sleep Medicine Network

Respiratory-related Sleep Disorders Section

Home sleep apnea test: Peripheral arterial tonometry

OSA is associated with serious health consequences and increased health care utilization (Kapur V, et al. Sleep. 1999:22[6]:749).

Polysomnography (PSG) is the gold standard for diagnosis, but is expensive, cumbersome, and inconsistently accessible. Home sleep apnea test (HSAT) devices provide a cost effective, convenient method to diagnose OSA and are non-inferior to PSG when considering treatment outcomes in uncomplicated adults with suggestive symptoms (Kapur VK, et al. J Clin Sleep Med. 2017;13[3]:479; Skomro RP, et al. Chest. 2010;138[2]:257).

Utilization of HSAT devices has increased in recent years, partly due to the COVID-19 pandemic and limitations in insurance reimbursement for PSG as the initial diagnostic test. But while there are benefits to home testing with respect to convenience and increased access, we must take the clinical context into account.

Peripheral arterial tonometry (PAT) is a commonly used HSAT technology, which measures peripheral arterial vascular tone using plethysmography at the fingertip. It has a sensitivity of 80% and specificity of 83% for detecting OSA in patients without significant comorbidities and high pretest probability of OSA compared to PSG (Ward KL, et al. J Clin Sleep Med. 2015;11[4]:433). But PAT has also been criticized for lacking diagnostic accuracy, particularly when including patients with mild OSA in analysis (Ichikawa M, et al. J Sleep Res. 2022;31[6]:e13682).

HSAT devices using PAT technology have been studied in patients with atrial fibrillation (Tauman R, et al. Nat Sci Sleep. 2020;12:1115), adolescents (Choi JH, et al. J Clin Sleep Med. 2018;14[10]:1741), and pregnant women (O’Brien LM, et al. J Clin Sleep Med. 2012;8[3]:287), and to assess OSA treatment adequacy with varying sensitivity and specificity. Study in special populations may allow for increased access to testing with the benefit of increased recognition of a generally underdiagnosed disorder. But it’s important to use HSAT alongside awareness of its limitations and it should not replace good clinical judgment when making treatment decisions.

Dimple Tejwani, MD

Member-at-Large

Kara Dupuy-McCauley, MD

Member-at-Large

Diffuse Lung Disease and Transplant Network

Pulmonary Physiology and Rehabilitation Section

Pulmonary rehabilitation (PR) is an essential component of the management of chronic pulmonary disease. Interest in alternate PR delivery methods has grown in recent years. The official workshop report of the American Thoracic Society (Holland AE, et al. Ann Am Thorac Soc. 2021;18[5]:e12) identified 13 essential components of PR in response to new program models. They encompass patient assessment, program content, method of delivery, and quality assurance, and serve as a guide for successful implementation of emerging programs.

A recent study reported significant improvement in COPD Assessment Test (CAT) scores after PR in both in-person (n=383) and virtual programs (n=171). Similar improvements were found in health outcomes, attendance, and dropout rate (Huynh VC, et al. Chest. 2023;163[3]:529). Another concurrent 3-year prospective study enrolled COPD patients in standard PR (n=89) or community based tele-PR (n=177) at seven tele-sites and one standard site (Alwakeel AJ, et al. Ann Am Thorac Soc. 2022;19[1]:39).

This study established the accessibility, feasibility, and safety of a community based tele-PR program and noted no differences between groups in 6-minute walk test or CAT score improvement. On follow-up, only tele-PR participants had persistent improvements of CAT scores beyond 1 month after completion.

Ongoing challenges with tele-PR include standardization of programs and of initial clinical evaluations that determine eligibility for them. Patients on home oxygen and those with exercise desaturation are often excluded, but they have the most potential for improvement. Studies are needed to determine the characteristics of patients who would benefit most from non-traditional models of PR.

Fatima Zeba, MD

Fellow-in-Training

Rania Abdallah, MD

Member-at-Large

Malik Khurram Khan, MD

Member-at-Large

Diffuse Lung Disease and Transplant Network

Pulmonary Physiology and Rehabilitation Section

Pulmonary rehabilitation (PR) is an essential component of the management of chronic pulmonary disease. Interest in alternate PR delivery methods has grown in recent years. The official workshop report of the American Thoracic Society (Holland AE, et al. Ann Am Thorac Soc. 2021;18[5]:e12) identified 13 essential components of PR in response to new program models. They encompass patient assessment, program content, method of delivery, and quality assurance, and serve as a guide for successful implementation of emerging programs.

A recent study reported significant improvement in COPD Assessment Test (CAT) scores after PR in both in-person (n=383) and virtual programs (n=171). Similar improvements were found in health outcomes, attendance, and dropout rate (Huynh VC, et al. Chest. 2023;163[3]:529). Another concurrent 3-year prospective study enrolled COPD patients in standard PR (n=89) or community based tele-PR (n=177) at seven tele-sites and one standard site (Alwakeel AJ, et al. Ann Am Thorac Soc. 2022;19[1]:39).

This study established the accessibility, feasibility, and safety of a community based tele-PR program and noted no differences between groups in 6-minute walk test or CAT score improvement. On follow-up, only tele-PR participants had persistent improvements of CAT scores beyond 1 month after completion.

Ongoing challenges with tele-PR include standardization of programs and of initial clinical evaluations that determine eligibility for them. Patients on home oxygen and those with exercise desaturation are often excluded, but they have the most potential for improvement. Studies are needed to determine the characteristics of patients who would benefit most from non-traditional models of PR.

Fatima Zeba, MD

Fellow-in-Training

Rania Abdallah, MD

Member-at-Large

Malik Khurram Khan, MD

Member-at-Large

Diffuse Lung Disease and Transplant Network

Pulmonary Physiology and Rehabilitation Section

Pulmonary rehabilitation (PR) is an essential component of the management of chronic pulmonary disease. Interest in alternate PR delivery methods has grown in recent years. The official workshop report of the American Thoracic Society (Holland AE, et al. Ann Am Thorac Soc. 2021;18[5]:e12) identified 13 essential components of PR in response to new program models. They encompass patient assessment, program content, method of delivery, and quality assurance, and serve as a guide for successful implementation of emerging programs.

A recent study reported significant improvement in COPD Assessment Test (CAT) scores after PR in both in-person (n=383) and virtual programs (n=171). Similar improvements were found in health outcomes, attendance, and dropout rate (Huynh VC, et al. Chest. 2023;163[3]:529). Another concurrent 3-year prospective study enrolled COPD patients in standard PR (n=89) or community based tele-PR (n=177) at seven tele-sites and one standard site (Alwakeel AJ, et al. Ann Am Thorac Soc. 2022;19[1]:39).

This study established the accessibility, feasibility, and safety of a community based tele-PR program and noted no differences between groups in 6-minute walk test or CAT score improvement. On follow-up, only tele-PR participants had persistent improvements of CAT scores beyond 1 month after completion.

Ongoing challenges with tele-PR include standardization of programs and of initial clinical evaluations that determine eligibility for them. Patients on home oxygen and those with exercise desaturation are often excluded, but they have the most potential for improvement. Studies are needed to determine the characteristics of patients who would benefit most from non-traditional models of PR.

Fatima Zeba, MD

Fellow-in-Training

Rania Abdallah, MD

Member-at-Large

Malik Khurram Khan, MD

Member-at-Large