A total of 270 patients planned for conventionally fractionated definitive doses (≥45 Gy) of RT were identified. The baseline patient, tumor and treatment characteristics are summarized in Table 1. Median age was 66.6 years (range 31-88 years), 50.4% were male (n=136), and 60.4% were partnered (n=163). 62.2% of patients were Caucasian (n=162) and 28.1% were black (n=76). The majority of patients were treated for newly diagnosed stage I-III disease (76.3%, n=206) with 3.7% stage I (n=10), 9.3% stage II (n=25) and 63.3% stage III (n=171); 11.9% had metastatic disease (n=32) and 11.9% had treatment for recurrent lung cancer (n=32) at the time of radiation. The most common histology was adenocarcinoma (53.3%, n=144), followed by squamous cell (32.6%, n=88), other NSCLC histology (10%, n=27), and then small cell (4.1%, n=11).
86.7% (n=234) of patients received concurrent chemotherapy, of which 60.3% (n=141/234) received full dose chemotherapy and 39.7% (n=93/234) received sensitizing chemotherapy. Median planned treatment dose was 63 Gy (range 45-72 Gy) with a median of 33 fractions (range 21-37).
Frailty Markers
A majority of patients had an ECOG performance status of 0-1 (n=229/257, 89%); 10% (n=26/257) of patients had ECOG of 2 and only 1% (n=2/257) had an ECOG of 3. Comorbidities were measured using the Charlson Comorbidity Index (CCI) with a median score of 5 (range 2-16). A majority of patients did not report weight loss at the time of consultation or start of treatment (63%, n=169). Median baseline BMI was 25.8 mg/m2 with a range of 15.0 to 51.5 mg/m2. Other baseline labs evaluated included hemoglobin (median 12.5 g/dL, range 7.8-18.2), creatinine (median 0.9 mg/dL, 0.3-4.4), and albumin (median 3.7 g/dL, 2.3-4.8).
Cancer-Related Hospitalization
Among the population, there was a 17% (n=47/270) rate of cancer-related hospitalization with 21% of those hospitalized (n=10/47) having >1 hospitalization within 30 days of completing RT. Hospitalizations ranged from 1 day after the start of treatment to 24 days after completing treatment with a median admission date of 31 days after starting treatment (Interquartile range (IQR): 16-47 days after start of RT). Univariable analysis of baseline variables associated with hospitalization are outlined in Table 1. On univariable analysis, hemoglobin of ≤10 was associated with 3 times higher risk of hospitalization compared to hemoglobin >10 (odds ratio (OR) 3.3, 95% confidence interval (CI) 1.4-7.9, P=0.01). Lower albumin was also associated with an increased risk of hospitalization. For each 1 g/dL baseline drop in albumin, there was a 3 times higher risk of hospitalization (OR 3.1, 95% CI 1.6-5.9, P=0.001). Baseline variables and frailty markers associated with >1 hospitalization are shown in Supplemental Table 1. On univariable analysis, lower baseline albumin with associated with a higher number of hospitalizations (coefficient 2.1, 95% CI 1.3-3.3, P=0.002) as was hemoglobin ≤10 (coefficient 3.1, 95% CI 1.7-5.4, P<0.001), BMI≤20 (coefficient 2.2, 95% CI 1.2-4.1, p=0.02), and squamous histology (coefficient 1.8, 95% CI 1.1-3.2, p=0.03).
The variables predicting for any hospitalization as well as number of hospitalizations (i.e. >1 hospitalization) selected in multivariable modeling are shown in Table 2. On multivariable analysis, lower albumin and hemoglobin ≤10 remained statistically significant. Hemoglobin ≤10 was associated with 2.4 times higher risk of hospitalization (95% CI 0.8-7.1, P=0.11) and on average, 2.7 more hospitalizations than having a hemoglobin >10 (95% CI 1.3-5.4, P=0.01). Each 1 g/dL drop in albumin was associated with a 2.4 times higher risk of hospitalization (95% CI 1.2-5.0, P=0.01) as well as increased number of hospitalizations (coefficient 1.5, 95% CI 0.9-1.5, P=0.11) after adjusting for other baseline patient, tumor, and treatment related variables.
Figure 1 shows a nomogram model predicting the risk of cancer-related hospitalization during or within 30 days of treatment. This model includes ECOG, hemoglobin, and albumin, which were the variables selected on multivariable modeling from amongst the baseline clinical frailty markers. As an example, this model would predict a patient with ECOG 2, hemoglobin 9 g/dL, and albumin of 3 g/dL, would have around a 55% risk of hospitalization.
Figure 2 shows the relationship between number of risk factors and rate of hospitalization. Risk factors included the same frailty markers as above but as categorical variables: ECOG ≥2, hemoglobin ≤ 10, and albumin ≤ 3.5. There was a significant association between number of risk factors and rate of hospitalization (X2(3)=10.8, P=0.01). As the number of risk factors increased from 0 to 3, the percentage of patients hospitalized increased from 11.8% (n=18/152), to 21.1% (n=18/85), to 31% (n=9/29), and to 50% (n=2/4), respectively.
Survival
The median follow up was 17 months (range 0.6-102 months). Two and three year overall survival for the cohort was 68% and 64%, respectively. Table 3 shows univariable and multivariable analysis of overall survival. On unadjusted modeling, baseline factors associated with increased mortality included: increasing age (Hazard Ratio (HR) 1.0, 95% CI: 1.0-1.1, P=0.02), male gender (HR 1.7, 95% CI: 1.1-2.7, P=0.01), squamous histology (HR 1.6, 95% CI: 1.0-2.6, P=0.04), sensitizing compared to full dose chemotherapy (HR 2.0, 95% CI: 1.3-3.2, P=0.004), increasing ECOG (HR 1.7, 95% CI: 1.2-2.4, P=0.01), increasing CCI (HR 1.2, 95% CI: 1.1-1.3, P<0.001), BMI≤20 (HR 2.7, 95% CI: 1.5-4.8, P=0.001), hemoglobin ≤10 (HR 2.5, 95% CI: 1.4-4.5, P=0.002), and lower albumin (HR 3.2, 95% CI: 1.0-5.0, P<0.001). On unadjusted modeling, the risk of death was 1.8 times higher among those hospitalized during treatment compared to those who were not (95% CI 1.1-3.1, P=0.02). Kaplan-Meier curves for overall survival of those who were hospitalized and those who were not hospitalized are shown in Figure 3. The two year overall survival was 54% among those who were hospitalized compared to 70% among those who were not hospitalized.
After adjusting for potential cofounders using multivariable modeling, the variables which were still associated with increased mortality included: male gender (HR 2.1, 95% CI: 1.3-3.4, P=0.004), increasing ECOG (HR 1.6, 95% CI: 1.1-2.4, P=0.02), BMI ≤20 (HR 3.2, 95% CI: 1.7-6.1, P=0.001), and decreasing albumin (HR 2.9, 95% CI: 1.7-4.5, P<0.001). After controlling for other baseline variables including age, comorbidities, concurrent chemotherapy, and baseline hemoglobin, cancer-related hospitalization was still associated with 1.8 times increased risk of death (95% CI: 1.02-3.1, P=0.04).