Inpatient palliative chemotherapy is associated with high mortality and aggressive end-of-life care in patients with advanced solid tumors and poor performance status

Advanced and incurable solid tumors were defined as recurrent or metastatic tumors for which no treatment with curative intent was available. Therapies with curative intent include complete surgical resection, definitive chemoradiation, or systemic chemotherapy for germ cell tumors. We defined poor performance status as ECOG-PS ≥2 on the first day of treatment with PC. ECOG-PS was available for all patients in the institution per electronic patient chart. The cancer center where the study took place, ICESP, is one of the largest cancer centers of Latin America, with approximately 10,000 new cancer patients per year and 499 beds for patients’ hospitalization.

Patients were included if they had histologically confirmed advanced solid tumors, and had ECOG-PS 3–4 at the time of starting frontline PC, or had ECOG-PS ≥ 2 at the time of starting second or later lines of chemotherapy. The rationality for these inclusion criteria was to represent poor ECOG-PS patients that are usually not included in clinical trials. Patients with ECOG-PS 2 receiving first-line chemotherapy were not included since this is often considered a standard of care. Solid tumors were considered all non-hematological malignancies.

Exclusion criteria included highly chemo-sensitive histologies (germ cell tumors, ovarian serous adenocarcinoma, and small cell lung cancer) and primary tumors of the central nervous system (CNS). Patients with primary CNS tumors were excluded because they frequently present poor ECOG-PS due to neurologic deficits even at disease diagnosis. To obtain our sample, we reviewed data from all consecutive patients that received chemotherapy during hospitalization according to the hospital records and included those that met eligibility criteria. The medical records were available at the cancer center (ICESP) database. Accessing the database required a permission, which was obtained with the Research Center of ICESP.

Data was collected from the electronic medical records and included: age, gender, primary tumor site, clinical stage (based on imaging studies), number of metastatic sites, main symptom(s) at hospitalization, line of chemotherapy and regimen (single agent versus combination), Charlson Comorbidity Index score, and body mass index. Charlson Comorbidity Index is a scale used to predict mortality based on patient comorbidities [14]. Main symptom(s) at hospitalization were the symptoms related to the reason of hospitalization (e.g.: abdominal pain and obstipation in case of malignant bowel obstruction). Nausea, vomiting, diarrhea, obstipation and abdominal pain were grouped as gastrointestinal symptoms. Neurologic symptoms included headache, seizure, focal neurologic deficits, and altered level of consciousness.

Laboratory tests at admission were reviewed to determine the hemoglobin (Hb) levels, total leukocyte and lymphocyte count, creatinine (Cr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (Bb), and calcium levels. Data on additional procedures used during hospitalization and place of death were also collected. Additional procedures recorded were blood transfusions, palliative radiotherapy, surgical procedures and/or admission to the intensive care unit (ICU).

The primary endpoint of the study was 30-day survival rate from the start of the first inpatient chemotherapy cycle. Secondary endpoints included median survival, 60-day survival rate from the start of the first inpatient chemotherapy cycle, prognostic factors associated with survival, rate of additional procedures performed, and hospital discharge rate after starting chemotherapy.

The prognostic factors evaluated were sex, age, primary tumor site, number of sites of metastases (less than or equal to 2 vs greater than 2), main symptom that led to hospitalization, ECOG-PS (3–4 vs 2), body mass index and Charlson index (≤ 6 vs > 6 points), and laboratory abnormalities. The cutoff value for the number of sites of metastases was chosen based on previous studies suggesting that the presence of more than 2 metastatic sites is associated with shorter overall survival [15, 16]. As for the Charlson index, we decided to compare ≤6 vs > 6 points because most patients would have a score of at least 6 due to the diagnosis of a metastatic solid tumor.

The laboratory tests were categorized according to the presence or absence of the following laboratory abnormalities: anemia (defined by Hb < 10 g/dL), leukocytosis (leukocytes ≥10.000 per mm³), lymphopenia (lymphocytes ≤1500 per mm³), hypercalcemia (defined by ionized calcium ≥5.3 mEq/L or total corrected calcium ≥10.2 mg/dL), elevated liver function tests (LFT) (defined by AST or ALT ≥2.5 times upper limit of normal), renal impairment (defined by Cr ≥ 1.5 mg/dL), and elevated bilirubin (defined by total Bb ≥ 1.5 mg/dL). Both clinical and laboratory variables were categorized based on clinical relevance for interpretation of the results in the clinical setting. Information on the clinical variables was available for all patients since it is systematically registered in electronic records during hospitalization at ICESP. For the laboratory tests, the median value was used for missing value imputation. The rates of missing data for the laboratory variables ranged from 0 to 17%.

Descriptive statistics were used to summarize patient characteristics. The absolute and relative frequencies of clinical and demographic data were tabulated. Qualitative variables were presented as proportions and quantitative variables were presented as median and respective ranges.

Survival analysis was performed using the Kaplan-Meier method. Factors associated with 30-day mortality were evaluated with univariable and multivariable analysis by using Cox regression. Prognostic factors with P ≤ 0.10 in univariable analysis and with no association between each other were included in the multivariable model. The association between categorical variables was evaluated by using χ2 test. A two-tailed P value ≤0.05 was considered statistically significant. Statistical analyses were performed using Stata software, version 14 (StataCorp, Texas, USA).

A total of 979 patients with solid tumors received PC during hospitalization between 2014 and 2016. Of these, 228 consecutive patients fulfilled the eligibility criteria and were included in the analysis. The CONSORT diagram is presented in Fig. 1.

Median age was 56 years (range 21–79). The majority of patients were female (58%) and chemotherapy-naïve (66%). The most common primary tumor sites were gastrointestinal (49.6%) and breast (18.4%). The proportions of ECOG-PS 2, 3 and 4 were 21.9, 66.7, and 11.4%, respectively. The majority of patients had metastatic disease at presentation (N = 223; 97.8%), and only 5 patients (2.2%) had a locally advanced disease not amenable for treatment with curative intent. Patients were predominantly treated with a combination chemotherapy regimen (N = 173; 76%).

Patient characteristics are summarized in Table 1.

Median follow–up was 49 days (range 1–507 days). Two hundred and twenty-four patients had died (98.2%), and median overall survival was 38.5 days. 30-day and 60-day survival rates were 55.7 and 38.5%, respectively. Seventy-three patients (32%) died during the same admission in which PC was started. Thirty-one patients (13.8%) died in the intensive care unit (ICU), twenty-seven patients (12%) died in an inpatient hospice facility and two patients (0.8%) died at home.

Median duration of index hospitalization was 16 days (range 2–87 days). Eighty-six patients (37%) required invasive procedures during the index hospitalization, which included 68 patients (30%) that required intensive care unit admission and 37 (16%) that underwent surgical procedures. One hundred and three patients (45%) received blood transfusions, and 22 patients (9.6%) received palliative radiotherapy. Approximately 68% of patients (N = 155) were discharged from the hospital after receiving PC, and 100 patients (43.8%) received at least one more cycle of PC as an outpatient after the index hospitalization. Outcomes of interest are summarized in Table 2.

In univariable analysis, 30-day mortality was positively correlated with presence of gastrointestinal symptoms at admission (harzard ratio [HR]: 2.04, 95% confidence interval [CI] 1.07–3.88, p 0.029), ECOG-PS (3–4 vs 2) (HR 2.05, 95% CI 1.17–3.62, P = 0.012), hypercalcemia (HR 2.09, 95% CI 1.20–3.63, P = 0.008), elevated LFTs (HR 1.84, 95% CI 1.17–2.90, P = 0.008) and elevated bilirubin (HR 3.07, 95% CI 1.94–4.84, P = < 0.001).

Among these variables, only ECOG-PS, hypercalcemia, and elevated bilirubin met inclusion criteria for the multivariable model. Gastrointestinal symptoms and elevated LFTs were not included because they were positively correlated with elevated bilirubin (χ2 P = 0.003; and χ2 P <  0.001, respectively). In the multivariable analysis, three prognostic factors were independently associated with 30-day mortality: ECOG-PS (3–4 vs 2) (HR 2.01, 95% CI 1.14–3.53, P = 0.016), hypercalcemia (HR 2.19, 95% CI 1.26–3.80, P = 0.041), and elevated bilirubin (HR 3.17, 95% CI 2.00–5.01, P < 0.001).

The results for the univariable and multivariable analyses are summarized in Tables 3 and 4, respectively.