Jan 30, 2023
In this JCO Article Insights episode, Davide Soldato summarizestwo articles from the January 10th, 2023 Journal of ClinicalOncology issue: “Low-Intensity Chemotherapy for Early Breast Cancerin Older Women: Results From the Prospective Multicenter HOPETrial” and “Inflammation and Clinical Decline After AdjuvantChemotherapy: Results From the Hurria Older Patients ProspectiveStudy .” Both articles report on clinical outcomes of elderlypatients treated with chemotherapy for early-stage breastcancer.
Davide Soldato: Thank you for joining JCOArticle Insights. I'm Davide Soldato. Today I will beproviding summaries for two different articles focused on elderlypatients treated for early-stage breast cancer. Both articles arereported from the Hurria Older Patients With Breast Cancer Study.This study is also known as the HOPE Study, and it was amulticenter, prospective, study of patients aged 65 years and oldertreated with current standard (Neo)adjuvant chemotherapy regimensfor early-stage breast cancer. The study captured several detailedgeriatric clinical and treatment data from 500 patients that wererecruited between September 2011 and May 2017 in 16 sites acrossthe United States.
The first article is titled ‘Low-intensityAdjuvant Chemotherapy for Breast Cancer in Older Women’. Inthis article, Dr. Sedrak and colleagues used data from the HOPEStudy to investigate the incidence of chemotherapy administrationwith low relative dose intensity, associated risk factors, andrelationship with survival outcomes. Previous data already showedthat the receipt of chemotherapy with a low relative dose intensityis associated with inferior survival outcomes, and the commonlyused threshold to define a low relative dose intensity is 85%. Andthis same threshold was used inside of the study that I amreporting. Elderly patients that are treated with chemotherapy areat higher risk of receiving chemotherapy with low relative doseintensity because of toxicity. However, previous data on the topicwas mainly retrospective in nature and reported heterogeneous ratesof low relative dose intensity up to 75%. And also, littleinformation was available on risk factors and on the impact onsurvival outcomes. So, considering the paucity and the quality ofthe previous data and the potential clinical implication forsurvival outcomes, results of the HOPE Study are extremely relevantto clinical practice as they provide novel insight on the topicfrom a prospective multicenter study.
In the analysis that was reported in the January issue ofJCO, the authors excluded patients with HER-2 positivedisease, those receiving nonstandard chemotherapy regimens, andthose with upfront chemotherapy dose reduction. The final analyticcohort included 322 patients with a median age of 70 years, 44%with stage II, and 22% with stage III disease. Docetaxel andcyclophosphamide, and anthracycline-based chemotherapy, and thisone, either alone or with subsequent paclitaxel, were the mostcommonly used chemotherapy regimens. Additionally, 85% of patientsreceived a primary prophylaxis with G-CSF. Relative dose intensitywas variable in the study. More than half of the patients receivedfull course chemotherapy with 100% relative dose intensity.However, the incidence of low relative dose intensity in the HOPEstudy was still 21%, thus identifying a subset of patients whoreceived chemotherapy with a suboptimal dose intensity. The ratesof low relative dose intensity were higher for patients receivingeither anthracycline-based chemotherapy and those with a plannedtreatment duration over 12 weeks.
The authors developed a multivariable logistic regression modelwith stepwise selection to identify risk factors associated withlow relative dose intensity. The results of this analysis showedthat an age higher than 76 years, administration of anthracyclineand CMF-based regimens, and a physician-rated Karnofsky PerformanceStatus under 90 were associated with higher risk of low relativedose intensity ranging from 3 to 5 times greater compared toreference categories. Then the authors realized another model wherethey used the previously mentioned three variables, but they alsoadjusted for relevant clinical characteristics, including age,stage, liver and renal function, and also previous cardiovasculardisease. And in this model, the three variables that were observedpreviously— age, type of chemotherapy, and Karnofsky PerformanceStatus—remained significantly associated with higher risk ofreceiving chemotherapy with a low relative dose intensity.
Finally, the Authors evaluated the association between a lowrelative dose intensity and survival outcomes, specifically breastcancer-specific mortality, non-breast cancer-specific mortality,and overall survival. Patients who received the chemotherapy with alow relative dose intensity had a significantly lower overallsurvival, and this association persisted even after excludingpatients older than 76 years. A higher risk of both breast cancerand non-breast cancer mortality was observed in patients with lowrelative dose intensity chemotherapy. However, the number ofcause-specific events was too low to obtain statisticalsignificance for both these endpoints.
In conclusion, the study by Dr. Sedrak and colleagues providesseveral relevant information for clinical practice. First, the HOPEstudy demonstrates that the administration of chemotherapy toelderly patients while maintaining an appropriate relative doseintensity is feasible. However, 1 in 5 patients receivedchemotherapy with a low relative dose intensity. So the results ofthis study reinforced the need to identify upfront patients mostlikely to require dose reduction. And these patients should beproactively supported during the administration of chemotherapy toensure that appropriate toxicity management can reduce the risk oflow relative dose intensity.
Second, in the study, the authors observed a significantassociation between a low relative dose intensity and the CARG andCARG-BC scores. These scores were previously validated to predictchemotherapy toxicity. The presence of this association isimportant because it suggests that these validated scores can beused routinely in clinical practice to identify patients that mightbenefit from a comprehensive geriatric assessment to optimizecomorbidities treatments and assure optimal delivery ofchemotherapy.
Finally, longer follow-up will provide the opportunity toestablish if the higher mortality that was observed in the HOPEstudy in patients receiving chemotherapy with a low relative doseintensity is consequent to the low chemotherapy efficacy or to aclinical decline that might be consequent to chemotherapyitself.
I will now move to the second article titled ‘Inflammationand Clinical Decline After Adjuvant Chemotherapy in Older AdultsWith Breast Cancer’. This article was published by Dr. Ji andcolleagues, and it describes a secondary analysis of the HOPEstudy. In this specific manuscript, the authors wanted to evaluatethe potential predictive role of baseline inflammatory biomarkerson the risk of clinical decline after administration ofchemotherapy. In the HOPE study, the authors collected informationon frailty stages, pre and post-chemotherapy using theDeficit-Accumulation Index (DAI): this is a 50-item scale thatevaluates deficits in physical activity of daily living,instrumental activities of daily living, psychosocial status,nutrition, frequency of falls, number of medications, comorbidconditions, social support, and laboratory values. The inflammatorybiomarkers that were evaluated in the current study were CRP andIL-6, and their levels were determined on pre-chemotherapy bloodspecimens. Using the deficit accumulation index score, patientswere categorized pre-chemotherapy as being robust, pre-frail, orfrail; this is important because previous studies alreadydemonstrated that there is a significant association between thiscategorization and morbidity and mortality outcomes in olderadults.
The primary outcome of the study was a chemotherapy-inducedclinical decline that was defined as a decline from a robust stagepre-chemotherapy to a pre-frail or frail status after chemotherapy.The overall analytic cohorts included 295 robust women. The medianage was 69, 62% of patients had stage II or III disease, mediannumber of comorbidities was 1.9, and mean BMI was 28.5. One in 4older women included in the study experienced achemotherapy-induced decline in frailty status, so this means thatthey transitioned from a robust status pre-chemotherapy to apre-frail or frail status after chemotherapy. This decline infrailty status was more frequent among patients with a higher BMI,those with more comorbidities, and those with stage II and IIIdisease.
Additionally, the patients who experienced chemotherapy-induceddecline had higher baseline levels of both IL-6 and CRP. Univariateanalysis also showed that patients with high IL-6 and CRP had athreefold higher risk of experiencing chemotherapy-induced declinein frailty stages. This association between higher inflammation andthe decline in frailty status remained significant in amultivariable logistic regression analysis that was adjusted forrelevant clinical and demographic characteristics, including age,stage, race, education, BMI, breast cancer surgery,anti-inflammatory medication, and number of comorbidities.Specifically, the results of these models showed that patients whohad both high CRP and IL-6 at baseline had a threefold higher riskof experiencing a decline in frailty status.
So, in conclusion, this study shows a significant associationbetween systemic inflammation and a decline in frailty status inelderly patients receiving chemotherapy for early-stage breastcancer. From a biological perspective, these higher levels ofsystemic inflammation might be a direct byproduct of a moreadvanced biological aging following the accumulation of senescentcells. There are several intriguing future perspectives that comefrom this study. First, if validated in additional cohorts, thesefindings might lead to higher treatment personalization thanks tothe identification of patients at risk of clinical decline based onclinical characteristics but also on systemic inflammation. Andthese patients could be then proactively supported duringchemotherapy to try and reduce the appearance of the clinicaldecline. Second, we know that inflammation is a potentiallytargetable pathway, and previous data obtained in breast cancerpatients showed the potential of behavioral, exercise, and dietaryinterventions in modulating systemic inflammation. So, based onthis new information, if validated in additional cohorts, futureresearch should then evaluate if this interventions can be used totreat and eventually prevent the decline in frailty status inpatients with high baseline systemic inflammation before receivingchemotherapy.
This is Davide Soldato in this episode of JCO ArticleInsights. We discussed two publications: ‘Low-intensityAdjuvant Chemotherapy for Breast Cancer in Older Women: Resultsfrom the Prospective Multicenter HOPE Trial’, and the secondone, ‘Inflammation and Clinical Decline After Adjuvant Chemotherapyin Older Adults with Breast cancer: Results from the Hurria OlderPatients Prospective Study’.
Thank you for your attention, and stay tuned for the nextepisode.
The purpose of this podcast is to educate andto inform. This is not a substitute for professional medical careand is not intended for use in the diagnosis or treatment ofindividual conditions.
Guests on this podcast express their ownopinions, experience, and conclusions. Guests' statements on thepodcast do not express the opinions of ASCO. The mention of anyproduct, service, organization, activity, or therapy should not beconstrued as an ASCO endorsement.
Like, share and subscribe soyou never miss an episode and leave a rating or review.
Low-intensityAdjuvant Chemotherapy for Breast Cancer in Older Women
Inflammationand Clinical Decline After Adjuvant Chemotherapy in Older AdultsWith Breast Cancer
Find more articles from the January 10 issue.