Impact of Pretreatment Weight Loss on Radiotherapy Utilization and Clinical Outcomes in Non-Small Cell Lung Cancer.

BACKGROUND: Cancer cachexia is a syndrome of unintentional weight loss resulting in progressive functional impairment. Knowledge of radiation therapy utilization in patients with cancer cachexia is limited. We evaluated the use of curative and palliative-intent radiation for the management of patients with non-small cell lung cancer (NSCLC) with cachexia to determine whether tumor-directed therapy affected cachexia-associated outcomes. METHODS: Using an Institutional Tumor Registry, we evaluated all patients with stages of NSCLC treated at a tertiary care system from 2006 to 2013. We adopted the international consensus definition for cachexia, with staging designated by the registry and positron emission tomography. Radiotherapy delivery and intent were retrospectively assessed. RESULTS: In total, 1330 patients with NSCLC were analyzed. Curative-intent radiotherapy was utilized equally between patients with cachexia and non-cachexia with stages I to III NSCLC. Conversely, significantly more patients with stage IV disease and cachexia received palliative radiotherapy versus those without (74% vs 63%, P = 0.006). Cachexia-associated survival was unchanged irrespective of tumor-directed radiation therapy with curative or palliative intent. In fact, pretreatment cachexia was associated with reduced survival for patients with stage III NSCLC receiving curative-intent radiotherapy (median survival = 23.9 vs 15.0 mo, P = 0.009). Finally, multivariate analysis identified pretreatment cachexia as an independent variable associated with worsened survival (hazard ratio = 1.31, CI: 1.14,1.52). CONCLUSION: Patients with advanced NSCLC with cachexia received more palliative-intent radiation than those without weight loss. Tumor-directed therapy in either a curative or palliative approach failed to alter cachexia patient survival across all stages of the disease. These findings offer critical information on the appropriate utilization of radiation in the management of patients with NSCLC with cachexia.

A preponderance of gastrointestinal cancer patients transition into cachexia syndrome.

BACKGROUND: Cancer cachexia is frequently documented by self-reported, single time-point weight histories. This approach lacks the granularity needed to fully elucidate the progression of cachexia syndrome. This study aimed to longitudinally assess body weight changes pre- and post-cancer diagnosis in gastrointestinal (GI) cancer patients. METHODS: Body weights and relevant clinical data recorded in the electronic health record 12 months pre- and post-GI cancer (colorectal, gastroesophageal, hepatobiliary and pancreatic) diagnosis were extracted. Weight loss was categorized by the International Consensus Definition for cachexia. RESULTS: A total of 879 patients were included in the final cohort including patients diagnosed with colorectal (n = 317), hepatocellular (n = 185), biliary (n = 72), pancreatic (n = 186) or gastroesophageal (n = 119) cancer. Stage of disease was equally distributed. Patients without cachexia at diagnosis (n = 608) remained weight stable during the 12 months pre-diagnosis (+0.5 ± 0.5% body weight; P = 0.99). Patients with cachexia at diagnosis (n = 271) remained weight stable 6 to 12 months prior to diagnosis (+0.4 ± 0.8%; P > 0.9999) and lost 8.7 ± 0.6% (P < 0.0001) within the 6 months pre-diagnosis. Patients without cachexia at diagnosis lost more weight post-diagnosis (6.3 ± 0.6%) than patients with cachexia at diagnosis (4.7 ± 1.0%; P = 0.01). Pre-diagnosis weight trajectories did not differ between primary malignancies or stage of disease in patients without or with cachexia at diagnosis (all P ≥ 0.05). Post-diagnosis weight trajectories did differ by primary malignancy (P ≤ 0.0002) and stage (P < 0.0001). In both patients without and with cachexia at diagnosis, colorectal patients lost the least amount of weight post-diagnosis and gastroesophageal patients lost the most amount of weight post-diagnosis. Stage 4 patients without or with cachexia at diagnosis lost the most weight post-diagnosis (P ≤ 0.0003). Regardless of cachexia status at diagnosis, patients lost more weight when treated with systemic therapy (7.1 ± 0.7%; P < 0.0001; n = 419) or radiation therapy (8.4 ± 1.4%; P = 0.02; n = 116) compared to those who did not. Patients who did not have surgery lost more weight post-diagnosis (7.6 ± 1.1%; P < 0.0001; n = 355) compared to those who did have surgery. By 12 months post-diagnosis, 83% of the surviving GI cancer patients in this cohort had transitioned into cachexia syndrome. CONCLUSIONS: Significant weight loss in patients with GI cancer cachexia at diagnosis initiates at least 6 months prior to diagnosis, and most patients will transition into cachexia syndrome post-diagnosis, regardless of pre-diagnosis weight change and stage of disease. These findings punctuate the importance of weight surveillance in cancer detection and earlier palliative interventions post-diagnosis in the GI cancer patient population.

Primary Tumor Fluorine-18 Fluorodeoxydglucose (18F-FDG) Is Associated With Cancer-Associated Weight Loss in Non-Small Cell Lung Cancer (NSCLC) and Portends Worse Survival.

Aim: To investigate the diagnostic potential of and associations between tumor 18F-FDG uptake on PET imaging and cancer-associated weight loss. Methods: 774 non-small cell lung cancer (NSCLC) patients with pre-treatment PET evaluated between 2006 and 2014 were identified. Using the international validated definition of cachexia, the presence of clinically significant pretreatment cancer-associated weight loss (WL) was retrospectively determined. Maximum Standardized Uptake Value (SUVMax) of 18F-FDG was recorded and dichotomized based on 3 experimental cutpoints for survival analyses. Each SUVMax cutpoint prioritized either survival differences, total cohort comparison sample sizes, or sample size by stage. Patient outcomes and associations between SUVMax and cancer-associated weight loss were assessed by multivariate, categorical, and survival analyses. Results: Patients were found to have an increased likelihood of having WL at diagnosis associated with increasing primary tumor SUVMax after controlling for potentially confounding patient and tumor characteristics on multivariate logistic regression (OR 1.038; 95% CI: 1.012, 1.064; P=0.0037). After stratifying the cohort by WL and dichotomized SUVMax, both factors were found to be relevant in predicting survival outcomes when the alternative variable was constant. Of note, the most striking survival differences contributed by WL status occurred in high SUVMax groups, where the presence of WL predicted a median survival time detriment of up to 10 months, significant regardless of cutpoint determination method applied to categorize high SUVMax patients. SUVMax classification was found to be most consistently relevant in both WL and no WL groups. Conclusions: The significant positive association between significant pretreatment cancer-associated weight loss and primary tumor SUVMax underscores increased glucose uptake as a component of catabolic tumor phenotypes. This substantiates 18F-FDG PET analysis as a prospective tool for assessment of cancer-associated weight loss and corresponding survival outcomes. Furthermore, the survival differences observed between WL groups across multiple SUVMax classifications supports the importance of weight loss monitoring in oncologic workups. Weight loss in the setting of NSCLCs with higher metabolic activity as determined by 18F-FDG PET signal should encourage more aggressive and earlier palliative care interventions.

Associations of Prior Chronic Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Glucocorticoids With Cachexia Incidence and Survival.

Background: Cachexia is an inflammatory and metabolic syndrome of unintentional weight loss through depletion of muscle and adipose tissue. There is limited knowledge of how chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids affect cachexia development. The purpose of this study was to investigate associations between prior long-term use of NSAIDs or glucocorticoids with cachexia incidence and post-diagnosis weight loss progression in a retrospective cancer patient cohort. Methods: Of 3,802 lung or gastrointestinal cancer patient records, 3,180 comprised our final cohort. Patient demographic information, tumor qualities, medication histories, and comorbidities were assessed. Cachexia was defined as having developed prior to oncologic treatment. Statistical evaluations included categorical, multivariate logistic regression, and log-rank survival analyses. Development of substantial post-diagnosis weight loss was calculated and interpreted for patients without cachexia at diagnosis. Results: Chronic prior use of any NSAID or glucocorticoid medication was associated with approximate absolute and relative reductions in cachexia incidence at diagnosis of 10 and 25 percent (P<0.0001). In multivariate analyses, NSAID medications demonstrated a 23 percent reduction in cachexia incidence likelihood (OR=0.770; 95% CI=0.594, 0.998; P=0.0481). Patients without cachexia at diagnosis were significantly more likely to develop substantial post-diagnosis weight loss from pre-diagnosis use groups of glucocorticoids (OR= 1.452; 95% CI=1.065, 1.979; P=0.0183) or NSAIDs (OR=1.411; 95% CI=1.082, 1.840; P=0.011). Conclusions: Our findings suggest a protective effect of prior anti-inflammatory medications, primarily NSAIDs, against manifestations of the cachexia phenotype at cancer diagnosis. These observations support further exploration of potential therapeutic benefits from anti-inflammatory medications early in cancer management.

Dose-Intensified Stereotactic Ablative Radiation for Localized Prostate Cancer.

Purpose: Stereotactic ablative radiation (SAbR) has been increasingly used in prostate cancer (PCa) given its convenience and cost efficacy. Optimal doses remain poorly defined with limited prospective comparative trials and long-term safety/efficacy data at higher dose levels. We analyzed toxicity and outcomes for SAbR in men with localized PCa at escalated 45 Gy in 5 fractions. Methods and Materials: This study retrospectively analyzed men from 2015 to 2019 with PCa who received linear-accelerator-based SAbR to 45 Gy in 5 fractions, along with perirectal hydrogel spacer, fiducial placement, and MRI-based planning. Disease control outcomes were calculated from end of treatment. Minimally important difference (MID) assessing patient-reported quality of life was defined as greater than a one-half standard deviation increase in American Urological Association (AUA) symptom score after SAbR. Results: Two-hundred and forty-nine (249) low-, intermediate-, and high-risk PCa patients with median follow-up of 14.9 months for clinical toxicity were included. Acute urinary grade II toxicity occurred in 20.4% of patients. Acute grade II GI toxicity occurred in 7.3% of patients. For follow-up > 2 years (n = 69), late GU and GI grade ≥III toxicity occurred in 5.8% and 1.5% of patients, respectively. MID was evident in 31.8%, 23.4%, 35.8%, 37.0%, 33.3%, and 26.7% of patients at 3, 6, 12, 24, 36, and 48 months, respectively. The median follow-up for biochemical recurrence was 22.6 months with biochemical failure-free survival of 100% at 1 year (n = 226) and 98.7% for years 2 (n = 113) and 3 (n = 54). Conclusions: SAbR for PCa at 45 Gy in 5 fractions shows an encouraging safety profile. Prospective studies with longer follow-up are warranted to establish this dose regimen as standard of care for PCa.

The influence of tumour fluorodeoxyglucose avidity and cachexia development on patient survival in oesophageal or gastroesophageal junction cancer.

Background and Aims: Cancer cachexia is manifested by loss in muscle, adipose, weight, and appetite. PET 18F-FDG uptake identifies tumor metabolic and inflammatory changes, potentially associated with cachexia development. We examined if primary gastroesophageal tumor 18F-FDG uptake correlates with cachexia development and survival in cancer patients. Methods: One hundred twenty-six esophageal (n=87) and gastroesophageal junction (n=39) cancer patients, with a median age at diagnosis of 63 years (IQR 54-71), evaluated between 2006-2014 with pre-treatment PET imaging and cachexia determination at diagnosis were included in the study cohort (22.1% female; 6.7%, 24.4%, 50.4%, and 18.5% with tumor stage I, II, III, and IV respectively). Maximum primary tumor standardized uptake values (SUVMax) were obtained and dichotomized based off the calculated cut-point SUVMax of 8.5 (P=.0018). Associations between survival, cachexia development and primary tumor 18F-FDG uptake were evaluated using univariate and multivariate analyses. Results: Cancer-associated weight loss (cachexia) and primary tumor SUVMax at or above the statistically determined cut-point of 8.5 were present in 54% and 57% of patients, respectively. Primary tumor SUVMax above the cut-point was significantly associated with pre-treatment cancer-associated weight loss (P=.0033) and, in multivariate analysis, correlated with a 2.3-fold increased risk of death (95% CI 1.4, 3.7; P=.0010). When divided into cohorts defined by their combined cachexia and high versus low SUVMax tumor status, positive cachexia status or/and high SUVMax tumors were associated with similar significant decrements in survival. Conclusion: A positive association was present between cancer-associated weight loss and SUVMax of the primary tumor, suggesting greater glycolytic metabolism in gastroesophageal tumors that induce cachexia. This interpretation of routinely administered PET scans could lead to earlier categorization of patients with cachexia-inducing tumors. Both cachexia and high SUVMax status were independently associated with worsened survival outcomes, further supporting their prognostic relevance in patients with gastroesophageal cancer.

Upfront radiotherapy with brachytherapy for medically inoperable and unresectable patients with high-risk endometrial cancer.

OBJECTIVES: Comprehensive surgery with adjuvant therapy is standard of care for high-risk endometrial cancers, whereas upfront radiotherapy with brachytherapy is indicated for inoperable/unresectable patients, irrespective of risk. We evaluated outcomes for inoperable/unresectable patients with high-risk endometrial cancer (HREC: stage III and/or grade 3) and low-risk endometrial cancer (LREC: stage I/II and grade 1/2) treated with upfront radiotherapy. METHODS: Twenty-nine patients with inoperable/unresectable endometrial cancer were treated with upfront radiotherapy at an academic medical center from 2012 to 2019. Cancer-specific survival (CSS), overall survival (OS), and recurrence rates between patients with HREC and LREC were compared. RESULTS: Median follow-up was 17.0 months (range 3.7-54.0). Twenty cancers were stage I + II and nine were stage III. Twenty-one cancers were grade 1 + 2 and eight were grade 3. Thirteen patients (45%) had HREC. Twenty-five patients received radiotherapy/chemoradiotherapy for primary treatment, while 4 patients received chemoradiotherapy before surgery. All patients underwent high dose rate brachytherapy (HDR) with 7 receiving HDR alone and 22 receiving external beam radiation and HDR. Two-year CSS was 100% for both HREC and LREC patients (log-rank p = 0.32). There was no OS difference between HREC and LREC patients (2-year: 73% vs. 77%; log-rank p = 0.33). Four HREC and 1 LREC patients recurred with one local recurrence in each group. There were no acute grade ≥3 and two late grade ≥3 gastrointestinal/genitourinary toxicities. CONCLUSIONS: Upfront radiotherapy for inoperable/unresectable HREC patients was well tolerated with high local control and CSS rates. Upfront radiotherapy with brachytherapy remains important even for high-risk inoperable and unresectable endometrial cancer patients.

Addition of Iodinated Contrast to Rectal Hydrogel Spacer to Facilitate MRI-Independent Target Delineation and Treatment Planning for Prostate Cancer.

PURPOSE: Hydrogel spacers reduce rectal dose toxicity during prostate cancer radiation therapy. Current products require magnetic resonance imaging (MRI) for visualization during treatment planning, but MRI incompatibility and cost have prompted alternatives using computed tomography (CT). This case series evaluates the addition of iodinated contrast to hydrogel as such an alternative. METHODS AND MATERIALS: Three patients underwent rectal hydrogel spacer placement with iodinated contrast modification. CT was performed within 1 hour of injection and again 1 week later. MRI was obtained at the time of the second CT. Hydrogel delineation was compared between CT and MRI and between paired CT scans. RESULTS: Spacer enhancement was visible on CT immediately after hydrogel placement (mean Hounsfield units, 122; range, 52-193) but not at the second CT 1 week later (mean Hounsfield units, 8; range, -8 to 29). Delineated spacer volume did not significantly differ between immediate postprocedure CT and MRI ≥1 week later in 2 patients (patient 1: 16.6 vs 15.5 cm3; patient 2: 12.6 vs 14.7 cm3; paired t-test, P = .81). CONCLUSIONS: CT visualization of rectal hydrogel admixed with contrast is feasible and allows delineation of interface with rectum/prostate.

Impact of Socioeconomic Status on Pretreatment Weight Loss and Survival in Non-Small-Cell Lung Cancer.

PURPOSE: Socioeconomic status (SES) influences health care outcomes, but the influence of primary payer on cancer-associated wasting is unknown. We hypothesized that primary payer as an indicator of SES would influence pretreatment cancer-associated weight loss and treatment outcomes. MATERIALS AND METHODS: Retrospective review of medical records identified 1,366 patients with non-small-cell lung cancer (NSCLC) consecutively treated at a tertiary care health system between January 1, 2006 and December 31, 2013. Insurance status was obtained from an institutional tumor registry. Cancer-associated weight loss was based on the validated international consensus definition of cachexia. Multivariable regression analyses were used to identify prognostic factors of pretreatment cancer-associated weight loss and survival. RESULTS: The cohort included a representative group of patients with a median age at diagnosis of 64 years, 47% females, and 33% patients of nonwhite race. Pretreatment cancer-associated weight loss was present at the time of NSCLC diagnosis in 17%, 14%, 32%, and 38% of patients with stage I, II, III, and IV disease, respectively. Pretreatment cancer-associated weight loss was associated with increasing age at diagnosis, black race, single marital status, tobacco use, and disease stage. Compared with private insurance, Medicaid insurance (odds ratio, 2.17; 95% CI, 1.42 to 3.30) and lack of insurance (odds ratio, 2.32; 95% CI, 1.50 to 3.58) were associated with pretreatment cancer-associated weight loss. Among cachectic patients, comorbidity, histology, tumor grade, and disease stage were prognostic of survival on multivariable analysis; however, primary payer was not. CONCLUSION: Pretreatment cancer-associated weight loss is common in patients with NSCLC, and its presence is significantly associated with lower SES. However, among patients with pretreatment cancer-associated weight loss, SES was not predictive of survival. Early use of cancer cachexia-directed therapies may improve outcomes, and further study on the biologic mechanisms of cancer cachexia will provide novel therapeutic avenues.

Prevalence and Survival Impact of Pretreatment Cancer-Associated Weight Loss: A Tool for Guiding Early Palliative Care.

PURPOSE: Cancer-associated weight loss is associated with poor prognosis in advanced malignancy; however, its pretreatment prevalence and survival impact are inadequately described in large cohorts. Such data, stratified by tumor type and stage, may facilitate the optimal and timely allocation of complementary care, leading to improvements in patient survival and quality of life. METHODS: We performed a retrospective cohort study of 3,180 consecutively treated adult patients with lung or GI (including colorectal, liver, and pancreatic) cancer. Pretreatment cancer-associated weight loss was based on the international consensus definition of cachexia. Prevalence and survival impact of pretreatment cancer-associated weight loss were evaluated using the Kaplan-Meier method and compared using log-rank test. RESULTS: Cancer-associated weight loss was observed at the time of cancer diagnosis in 34.1% of patients. Pretreatment weight loss was documented in 17.6%, 25.8%, 36.6%, and 43.3% of stage I, II, III, and IV cancers, respectively. Wasting was common regardless of tumor type, with prevalence at diagnosis ranging from 27.3% in patients with colorectal cancer to 53.4% in patients with gastroesophageal cancer. Pretreatment weight loss was associated with reduced overall survival after adjusting for stage, size, grade, comorbidity, age, sex, and tobacco history (hazard ratio, 1.26; 95% CI, 1.13 to 1.39). CONCLUSION: Pretreatment cancer-associated weight loss is common, even in early-stage disease, and is independently associated with reduced survival. Minimal weight loss represents a clinically distinct entity with an associated overall survival intermediate to that of no weight loss and overt wasting. Early diagnosis and treatment of cancer-associated wasting offers a novel therapeutic avenue for reducing cancer mortality.