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. Author manuscript; available in PMC: 2020 Feb 1.
Published in final edited form as: J Thorac Oncol. 2018 Oct 15;14(2):176–183. doi: 10.1016/j.jtho.2018.09.029

Association of Early Palliative Care with Chemotherapy Intensity in Patients with Advanced Stage Lung Cancer:

A National Cohort Study

A Lammers 1,2, CG Slatore 3,4,5,6, EK Fromme 7,8, KC Vranas 4,3,6, DR Sullivan 4,3,6
PMCID: PMC6348039  NIHMSID: NIHMS1509735  PMID: 30336324

Introduction

In 2018, more than 234,000 Americans will be diagnosed with lung cancer, and the majority of these will be advanced stage disease.1,2 Despite advances in treatment for advanced stage patients, prognosis is poor, with median survival of less than one year.2,3 Palliative chemotherapy is initiated in patients with advanced lung cancer with a goal to improve quality of life (QOL) and survival, as it cannot cure disease. The American Society of Clinical Oncology (ASCO) recommends against chemotherapy in patients with an Eastern Cooperative Oncology Group (ECOG) score ≥3 and in those for whom there was no evidence of clinical value as it is both harmful and wasteful.4-6 Unfortunately, a considerable proportion of patients with poor performance status continue to receive chemotherapy, which is considered low quality cancer care.4,7

High-intensity chemotherapy among advanced lung cancer patients has not been well-defined. However, the National Comprehensive Cancer Network (NCCN) recommends no more than 4 cycles of a platinum-based doublet as the initial treatment in most patients with advanced lung cancer.8,9 Additionally, each subsequent line of chemotherapy has diminishing returns with one study showing third and fourth line response rates of 2% and 0%, respectively.10 Treatment with triplet therapy (bevacizumab or cetuximab combination) has a very high toxicity profile with inconsistent survival benefit, particularly among older patients.11 Also, while erlotinib is beneficial for a select group of patients with epidermal growth factor receptor (EGFR) mutations, prior to accessible confirmatory EGFR testing, response rates were very low and therapy was considered salvage.12,13 Chemotherapy near the end-of-life, namely in the last 14 and 30 days of life, is detrimental to patient QOL, satisfaction and increases hospitalization rates.14-18

Early palliative care (EPC) is recommended by ASCO guidelines as it improves symptom burden and QOL, and may reduce aggressive end-of-life care and increase survival.19,20 However, the mechanisms of these benefits are unclear. It has been hypothesized that palliative care may confer benefits via enhanced communication of patient preferences and symptom management, thus helping reduce unintended harms of high-intensity treatment leading to a potential survival benefit.21,22 Alternatively, another possibility is that the benefits of EPC are related to more judicious use of chemotherapy or high-intensity chemotherapy only for patients who are likely to derive benefit. The aims of this study were to characterize chemotherapy receipt among a national population of patients with advanced stage lung cancer in an integrated health system, and to determine the associations between EPC and both chemotherapy and high-intensity chemotherapy receipt.

Methods

Retrospective cohort study of Veterans diagnosed with advanced stage (IIIB or IV) lung cancer identified using the Veterans Affairs Central Cancer Registry (VACCR) between January 1, 2007-December 31, 2013. VACCR registrars’ abstract patient cases including sociodemographic, tumor characteristics and treatments received in accordance with the Commission on Cancer.23 Other patients characteristics, at the time of cancer diagnosis, were compiled from the VA Corporate Data Warehouse (CDW) which integrates clinical and administrative data. Cancer staging was determined using VACCR data and is based on the American Joint Committee on Cancer (AJCC) TNM staging system.2 Extensive stage small cell lung cancer (SCLC) was categorized as stage IV. Patients with non-primary lung cancer, unknown stage or histology, and initial chemotherapy receipt >180 days after cancer diagnosis were excluded. Late chemotherapy receipt (>180 after diagnosis) was not considered part of the initial treatment plan. Additional cohort characteristics have been described previously.24

Exposure

Early Palliative Care

Palliative care was defined as at least one specialty palliative care encounter received after a lung cancer diagnosis determined using VA administrative inpatient, outpatient, and fee-based encounter data. Current palliative care guidelines recommend “early” palliative care although, the timing of this has not been consistently defined. Therefore, in this study EPC was defined as an initial palliative care encounter received within 90 days of a lung cancer diagnosis based on previous studies.22,25-28

Outcomes

Chemotherapy Receipt

Chemotherapy receipt was obtained from the inpatient and outpatient pharmacy files in the CDW.29 Chemotherapy receipt was defined as any oral or intravenous antineoplastic therapy received after a lung cancer diagnosis. Receipt was captured as chemotherapy type, dose and route administered. The following drugs were considered chemotherapy: bevacizumab carboplatin, cetuximab, cisplatin, crizotinib, cyclophosphamide, docetaxel, doxorubicin, epirubicin, erlotinib, etoposide, gemcitabine, ifosfamide, irinotecan, nanoparticle albumin-bound paclitaxel, paclitaxel, pemetrexed, temozolamide, topotecan, vinblastine, and vinorelbine. The following agents were included, but not received by patients in our cohort: Afatinib, alectinib, cabozatinib, ceritinib, gefitinib, ipilumimab, nivolumab, pembrolizumab, necitumumab, ramicurimab, sorafenib, teniposide, vincristine and vindesine.

High-intensity Chemotherapy

High-intensity chemotherapy definitions were determined a priori and were based on ASCO guidelines and clinical trial data as described below:

  1. >4 cycles of a platinum-based doublet: Each cycle of platinum doublet was defined as receipt of carboplatin or cisplatin with an associated doublet drug (e.g., cyclophosphamide, docetaxel, doxorubicin, epirubicin, etoposide, gemcitabine, ifosfamide, irinotecan, nanoparticle albumin-bound paclitaxel, paclitaxel, pemetrexed, vinblastine, or vinorelbine). Each platinum cycle was defined as receipt of cisplatin or carboplatin and its associated doublet drug 14-36 days after the initial platinum drug. Randomized controlled trials found chemotherapy beyond 3-4 courses conveyed no survival or QOL benefits in advanced NSCLC.30-33

  2. ≥3 lines of chemotherapy: One line of chemotherapy was considered if at least one dose of a single antineoplastic drug (singlet) defined above, platinum doublet (doublet) or three drugs (triplet) chemotherapy (defined below) drug dose/combination. An additional line of chemotherapy was then considered for each transition to a new chemotherapeutic agent for at least 1 dose. Doublet combinations were based on the platinum base and if one antineoplastic was changed, it was considered a different line. Similarly, triplet therapy was based on receipt of bevacizumab or cetuximab combined with a platinum-doublet and if chemotherapy transitioned to doublet or singlet, it was considered a subsequent line. This definition was based on data demonstrating response rates in advanced NSCLC decrease with each successive line of treatment.10,13,34,35

  3. Triplet therapy: This was defined as ever receipt of Bevacizumab or Cetuximab combined with other neoplastic agents after a lung cancer diagnosis. The rationale for use of Bevacizumab to define chemotherapy intensity is historically based on four randomized control trials (RCTs) showing Bevacizumab did not improve one-year overall survival.11 These RCTs showed increased risk of treatment related death, especially in patients older than 65 years old. Cetuximab was also considered high intensity given its adverse safety profile and equivalent progression free survival compared to safer alternatives.36,37

  4. Erlotinib prior to 2011: Receipt of erlotinib prior to Jan 1, 2011 was considered intensive therapy as it was not likely guided by mutation testing and there was no evidence of benefit in wild-type EGFR patients. Only 93 (1.1%) of Veterans were tested for epidermal growth factor receptor (EGFR) mutations prior to 2011, and only 7% of Veterans from 70 VA medical center between 2011-2013 were found to have EGFR activating mutations.38,39 Furthermore, the FDA removed the indication for EGFR wild-type patients because of no improvement in progression free survival or overall survival with use.40

  5. Chemotherapy at the end of life: Defined as receipt of any antineoplastic agent within 14 or 30 days of death. Late chemotherapy is a marker of intensive oncology care and is associated with lower satisfaction, increased ICU use and less referral to hospice care when received within 14 days of life, all measures of low-quality cancer care.15,19,41,42

Statistical Analysis

Descriptive statistics were used to characterize patient sociodemographics by chemotherapy receipt. Continuous data are presented as mean ±Standard Deviation (SD) or median (interquartile range (IQR)) and categorical variables as proportions. The association between EPC and receipt of chemotherapy was modeled using adjusted multivariable logistic regression. Chemotherapy high-intensity models only included those patients who received chemotherapy. Receipt of erlotinib included patients who received chemotherapy from 2007-2010. All regression models were adjusted for age, sex, race, marital status, income, tobacco use, year of cancer diagnosis, functional comorbidity index (FCI), Charlson comorbidity index (CCI), cancer stage, histology and survival recorded at the time of diagnosis.43,44 Receipt of chemotherapy at the end of life (14 & 30 days) excluded patients alive <14 days and <30 days, respectively and neither model was adjusted for survival. Sensitivity analyses were conducted to assess chemotherapy receipt using i) survival in overlapping intervals (i.e., 1-30 days, 1-60 days, 1-90 days, etc.); ii) excluding patients alive less than the mean of chemotherapy receipt (<60 days); and iii) timing of EPC before initial chemotherapy receipt or chemotherapy prior to EPC consult, results were similar to the final models. Modeling used robust standard errors and statistical testing was 2-sided with a threshold of p<0.05. All analyses were done in Stata version-14 (StataCorp).

Results

Overall, 23,566 patients were diagnosed with advanced stage lung cancer from 2007-2013, mean age was 68 years, 98% were men, 71% were white, 57% were not married, and 56% were current smokers. Regarding tumor characteristics, 89% had stage IV disease and 69% were diagnosed with NSCLC. (Table 1) Among the entire cohort, 37% (8,638/23,566) received EPC. Of those receiving EPC, the mean time from lung cancer diagnosis to first palliative care encounter was 26 days (Standard Deviation (SD) 24) and the mean time from first palliative care encounter to death was 105 days (SD 200). In the entire cohort, 12% (2832/23566) of patients received chemotherapy in the last 30 days and 6% (1365/23566) of patients received chemotherapy in the last 14 days of life.

Table 1.

Patient Characteristics

N = 23,566 Early Palliative Care
Yes
n = 8638		 No
n = 14,928
Age, years, mean (SD) 68 (10) 68 (9)
Sex, male 8509 (99) 14,619 (98)
Race
 White 6116 (71) 10,526 (71)
 Black 1316 (15) 2333 (16)
 Other 1206 (14) 2069 (14)
Marital status
 Married 3368 (39) 6805 (46)
 Not Married 5249 (61) 8097 (54)
 Unknown 21 (<1) 26 (<1)
Income, US dollars
 ≤44,000 2782 (32) 5204 (35)
 >44,000-52,999 2696 (31) 4626 (31)
 ≥53,000 3124 (36) 5043 (34)
 Unknown 36 (<1) 55 (<1)
Home residence
 Urban 6125 (71) 10,385 (70)
 Rural 2366 (27) 4348 (29)
 Unknown 147 (2) 195 (1)
FCI
 None (0) 2135 (25) 3074 (21)
 Mild (1-2) 1633 (19) 3543 (24)
 Moderate (3-4) 2378 (28) 4457 (30)
 Severe (≥5) 2492 (29) 3854 (26)
CCI
 None (0) 887 (10) 2091 (14)
 Mild (1-2) 1792 (21) 4399 (29)
 Moderate (3-4) 1742 (20) 3648 (24)
 Severe (≥5) 4217 (49) 4790 (32)
Tobacco history
 Never 229 (3) 441 (3)
 Current 4871 (56) 8280 (55)
 Former 3189 (37) 5571 (37)
 Unknown 349 (4) 636 (4)
AJCC cancer stage
 IIIB 632 (7) 2060 (14)
 IV 8006 (93) 12,868 (86)
Cancer histology
 NSCLC 5836 (68) 10,477 (70)
 SCLC 1514 (18) 2699 (18)
 Other 1288 (15) 1782 (12)
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Values reported as n (%) unless otherwise stated.

AJCC, American Joint Committee on Cancer; FCI, functional comorbidity index; CCI, Charlson comorbidity index.

Chemotherapy Characteristics

Overall, 45% (10,501/23,566) of patients received any chemotherapy, 34% and 51% among those with and without EPC, respectively. (Table 2) The mean time from diagnosis of lung cancer to first chemotherapy cycle was 36 days (SD 28) in those with EPC and 49 days (SD 37) in those without EPC. Among patient who received chemotherapy, the first cycle received was most commonly a platinum-based doublet in each group. The last chemotherapy cycle received was most often a platinum-based doublet in those with and without EPC 57% vs 45%, respectively. The duration from last chemotherapy dose to death was shorter in those with EPC, 83 days (SD 127), compared to 140 days (SD 229) in those without EPC.

Table 2.

Chemotherapy Characteristics

Early Palliative Care
Yes
n = 2907		 No
n = 7594
Diagnosis to first chemotherapy, days, mean (SD) 36 (28) 49 (37)
First chemotherapy regimen
 Singlet 271 (9) 637 (8)
 Doublet 2380 (82) 6102 (80)
 Triplet 112 (4) 477 (6)
 Erlotinib 144 (5) 378 (5)
Total platinum cycles,a mean (SD) 2.7 (2.1) 3.5 (2.3)
 Cisplatin 2.4 (1.8) 2.8 (1.8)
 Carboplatin 2.6 (2.0) 3.3 (2.2)
Dose Intensity, mean (SD)
 Cisplatin dose,b total mg/m2 195 (159) 224 (160)
 Carboplatin dose,c AUC 14 (15) 19 (17)
Last chemotherapy regimen
 Singlet 893 (31) 2754 (36)
 Doublet 1645 (57) 3382 (45)
 Triplet 85 (3) 303 (4)
 Erlotinib 284 (10) 1155 (15)
Interval of last chemotherapy to death, mean days (SD) 83 (127) 140 (229)
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Reported as n(%) unless otherwise stated.

a

Denominator= patients who received ≥1 cycle of platinum chemotherapy.

b

Denominator= patients who received ≥1 Cisplatin-based cycle.

c

Denominator= patients who received ≥1 Carboplatin based cycle.

note= mean total platinum cycles are not equal to the total cisplatinum and carboplatinum cycles as some patients received combinations of these agents

Any Chemotherapy and High-intensity Chemotherapy Receipt

Comparing patients with and without EPC, those with EPC were less likely to receive any chemotherapy (AOR 0.55, 95% CI: 0.51-0.58). (Table 3) Those with EPC were also less likely to receive >4 cycles of platinum-based doublet chemotherapy (AOR 0.68, 95% CI: 0.60-0.77) and ≥3 lines of chemotherapy (AOR 0.61, 95% CI: 0.53-0.71). Regarding chemotherapy regimens, triplet therapy (AOR 0.68, 95% CI: 0.56-0.82) receipt occurred less often in those with EPC compared to those without EPC. Finally, erlotinib prior to 2011 (AOR 0.66, 95% CI: 0.55-0.79) was also less likely to be received in the EPC group compared to the group without EPC. Surprisingly, patients with EPC were more likely to receive chemotherapy in the last 14 (AOR 1.65, 95% CI: 1.44-1.87) and 30 days (AOR 1.67, 95% CI: 1.51-1.85) of life compared to patients without EPC. Of those who received chemotherapy, 18% (518/2907) with EPC and 11% (847/7594) without EPC were treated in the last 14 days of life and 36% (1037/2907) with EPC and 24% (1795/7594) without EPC received chemotherapy in the last 30 days of life.

Table 3.

Association of Early Palliative Care and Chemotherapy

Unadjusted OR
(95% CI)		 p Adjusted OR
(95% CI)		 p
Any chemotherapy 0.49 (0.46–0.52) <.001 0.55 (0.51–0.58)a <.001
High-intensity chemotherapy
 i) >4 cycles platinum-based doublet 0.55 (0.50–0.62) <.001 0.68 (0.60–0.77)a <.001
Chemotherapy lines
 ii) ≥3 lines of chemotherapy 0.43 (0.37–0.49) <.001 0.61 (0.53–0.71)a <.001
Chemotherapy regimens
 iv) Triplet therapy everc 0.55 (0.46–0.66) <.001 0.68 (0.56–0.82)a <.001
 v) Erlotinib (before 2011) 0.51 (0.43–0.60) <.001 0.66 (0.55–0.79)a <.001
Timing of chemotherapy
 vi) Chemotherapy in last 14 days 1.73 (1.53–1.95) <.001 1.65 (1.44-1.87)b <.001
 vii) Chemotherapy in last 30 days 1.79 (1.63–1.97) <.001 1.67 (1.51–1.85)b <.001
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a

Adjusted by age, sex, race, marital status, income, tobacco history, residence rurality, CCI, FCI, cancer stage, histology, year of diagnosis, and overall survival.

b

Adjusted by age, sex, race, marital status, income, tobacco history, residence rurality, CCI, FCI, cancer stage, histology, and year of diagnosis.

c

Triplet therapy: bevacizumab or cetuzimab plus two-drug regimen.

CI, confidence interval; CCI, Charlson comorbidity index; FCI, functional comorbidity index.

Discussion

In a national cohort of patients with advanced lung cancer, EPC was associated with reduced receipt of chemotherapy. Additionally, EPC was associated with reduced receipt of high-intensity chemotherapy including four cycles of platinum-based therapy, three or more lines of chemotherapy, triplet therapy, and erlotinib prior to 2011, compared to patients without EPC. Surprisingly, EPC was associated with greater likelihood to receive chemotherapy at the very end of life. Among patients with advanced lung cancer, EPC may help optimize patient selection for receipt of any chemotherapy and especially, high-intensity chemotherapy by changing the focus to patients’ goals and QOL consistent with high-quality cancer care.

EPC is a key recommendation in ASCO’s guidelines given its potential benefits to QOL and survival; however, the mechanism(s) of these benefits are largely unknown. Previous studies suggest better symptom control or improvements in mental health as the main drivers of benefits 20,22,45 However, recent research suggests that patients with advanced cancer undergoing second-line chemotherapy have decrements in their QOL, especially among those with good performance status, and new chemotherapy initiation is less common when discussing treatment decisions.46,47 Yet, the relationship between EPC and chemotherapy receipt is complex. EPC may improve symptom control enabling patients to tolerate an increased number of cycles or lines of chemotherapy contributing to improved survival.22,48 Alternatively, as was found in our study, EPC was associated with reduced receipt of high-intensity chemotherapy, that can contribute to worse QOL and survival. Depending on a patient’s suitability and preference for chemotherapy, according to their goals of care, either of these roles could explain the improved patient outcomes observed with initiation of EPC in previous studies.22,25

Patient selection of those likely to derive benefit from chemotherapy or high-intensity chemotherapy regimens is challenging. We observed an association between EPC and reduced receipt of high-intensity chemotherapy, one of the first studies to examine this relationship with such granular chemotherapy details. The explanations for the observed relationship are likely multifactorial and EPC has several potentially important roles regarding patient selection for chemotherapy receipt: i) EPC may increase a patient’s ability to cope with their illness and simultaneously improve collaboration with oncology and palliative care thereby making decisions about chemotherapy discontinuation more tolerable;47 ii) EPC may assist in a more accurate assessment of performance status, identifying patients with lower ECOG scores, providing a realistic assessment of potential benefits and harms of chemotherapy;49 iii) practitioners who consult palliative care specialists early, may also be less likely to offer high-intensity care;50 and iv) more debilitated patients might generate earlier palliative care consults and inherently be less likely to receive higher intensity chemotherapy.51 Overall, our study highlights the importance of early integration of palliative care as part of a comprehensive cancer program, given its potential benefit in guiding appropriate patient selection for chemotherapy receipt.

The finding that EPC was associated with increased chemotherapy receipt in the last days of life was unexpected. The percentage of patients receiving chemotherapy close to death in our study was consistent with previously reported values in a study of Veterans with cancer which was significantly less than received by fee-for-service Medicare patients with cancer.52 Importantly, the VA allows Veterans to receive concurrent hospice care and chemotherapy which may contribute to late chemotherapy receipt in the EPC group.24 When we excluded patients with extremely shortened life expectancy, survival less than 90 days from diagnosis, the effect size for late chemotherapy receipt differences decreased, although significant differences persisted. EPC, when received close to cancer diagnosis, may be expected to have an impact on subsequent chemotherapy receipt and intensity. However, EPC may not actually reduce the likelihood of late chemotherapy as has been theorized, but not extensively studied in real-world populations of patients.15,19,20 A sub-analysis of a randomized trial of EPC found reduced chemotherapy in the last 60 days of life, however, chemotherapy characteristics (e.g., regimen intervals, number of regimens and dose intensity) were not compared due to significant sample heterogeneity.48 This same trial found no differences in receipt of chemotherapy in the last 14 and 30 days of life between patients in the EPC and control groups. Our results were consistent with these findings and demonstrate that the relationship between palliative care and chemotherapy receipt at the very end of life deserves further examination.

There are study limitations. Performance status was not consistently available via a score (e.g., Eastern Cooperative Oncology Group (ECOG)), therefore, we relied on surrogate markers including age, cancer stage, histology, CCI and FCI. There were few women included in the study which limit generalizability. Chemotherapy cycle delays limited assessments of some chemotherapy types as irregular cycle intervals prevented accurate cycle frequency counts. Oncologists’ reasons for chemotherapy delays or dose reductions were unavailable. Detailed chemotherapy data was limited to patients receiving cancer care within the VA, and some patients may have received additional chemotherapy outside of the VA. Although, it is rare to initiate concomitant chemotherapy in multiple care settings. We studied specialty palliative care encounters, not referrals, and patients’ preferences regarding palliative care were not captured. Palliative care delivered by non-palliative care specialists (e.g., primary care clinicians) was not studied.

Conclusions

Among patients with advanced lung cancer in a national integrated healthcare system, early palliative care was associated with reduced odds of receiving any or high-intensity chemotherapy. Early palliative care was also associated with increased receipt of chemotherapy at the very end of life. Early integration of palliative care may enhance patient selection for chemotherapy receipt by incorporating goals of care discussions, fostering better communication among the multidisciplinary care team, and setting realistic patient expectations for cancer treatment, leading to optimized patient selection of those most likely to derive benefit. Continued attention to the use of chemotherapy and high-intensity of chemotherapy in patients with advanced cancer is essential to improve the quality of comprehensive lung cancer care.

Acknowledgments

Note: This study was supported by the National Cancer Institute of the NIH under Award Number K07CA190706, the Health Services Research & Development, Center to Improve Veteran Involvement in Care (CIVIC) (CIN 13-404) at the VA Portland Health Care System (VAPORHCS) and the Department of Veterans Affairs. This work was supported using resources and facilities at the VA Informatics and Computing Infrastructure (VINCI),VA HSR RES 13-457, and VAPORHCS. Support for VA/CMS Data provided by the Department of Veterans Affairs, VA Health Services Research and Development Service, VA Information Resource Center (Project: Sullivan-01). The Department of Veterans Affairs did not have a role in the conduct of the study, in the collection, management, analysis, interpretation of data, or in the preparation of the manuscript. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs or the U.S Government.

Footnotes

Conflict of Interest Statement: All authors declare no conflicts of interest with the work presented in this manuscript.

Authorship Statement: All authors have made substantial contributions to the 1) conception and design, acquisition of data, or analysis and interpretation of data; 2) have contributed to drafting the article for important intellectual content; and 3) have provided final approval of the version to be published. Austin Lammers takes responsibility for the content of the manuscript, including data and analysis

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