Week 18 – Early Palliative Care in NSCLC

“Early Palliative Care for Patients with Metastatic Non-Small-Cell Lung Cancer”

N Engl J Med. 2010 Aug 19;363(8):733-42 [free full text]

Ideally, palliative care improves a patient’s quality of life while facilitating appropriate usage of healthcare resources. However, initiating palliative care late in a disease course or in the inpatient setting may limit these beneficial effects. This 2010 study by Temel et al. sought to demonstrate benefits of early integrated palliative care on patient-reported quality-of-life (QoL) outcomes and resource utilization.

The study enrolled outpatients with metastatic NSCLC diagnosed < 8 weeks ago and ECOG performance status 0-2 and randomized them to either “early palliative care” (met with palliative MD/ARNP within 3 weeks of enrollment and at least monthly afterward) or to standard oncologic care. The primary outcome was the change in Trial Outcome Index (TOI) from baseline to 12 weeks.

TOI = sum of the lung cancer, physical well-being, and functional well-being subscales of the Functional Assessment of Cancer Therapy­–Lung (FACT-L) scale (scale range 0-84, higher score = better function)

Secondary outcomes included:

  1. change in FACT-L score at 12 weeks (scale range 0-136)
  2. change in lung cancer subscale of FACT-L at 12 weeks (scale range 0-28)
  3. “aggressive care,” meaning one of the following: chemo within 14 days before death, lack of hospice care, or admission to hospice ≤ 3 days before death
  4. documentation of resuscitation preference in outpatient records
  5. prevalence of depression at 12 weeks per HADS and PHQ-9
  6. median survival

151 patients were randomized. Palliative-care patients (n=77) had a mean TOI increase of 2.3 points vs. a 2.3-point decrease in the standard-care group (n=73) (p=0.04). Median survival was 11.6 months in the palliative group vs. 8.9 months in the standard group (p=0.02). (See Figure 3 on page 741 for the Kaplan-Meier curve.) Prevalence of depression at 12 weeks per PHQ-9 was 4% in palliative patients vs. 17% in standard patients (p = 0.04). Aggressive end-of-life care was received in 33% of palliative patients vs. 53% of standard patients (p=0.05). Resuscitation preferences were documented in 53% of palliative patients vs. 28% of standard patients (p=0.05). There was no significant change in FACT-L score or lung cancer subscale score at 12 weeks.

Implication/Discussion:
Early palliative care in patients with metastatic non-small cell lung cancer improved quality of life and mood, decreased aggressive end-of-life care, and improved survival. This is a landmark study, both for its quantification of the QoL benefits of palliative intervention and for its seemingly counterintuitive finding that early palliative care actually improved survival.

The authors hypothesized that the demonstrated QoL and mood improvements may have led to the increased survival, as prior studies had associated lower QoL and depressed mood with decreased survival. However, I find more compelling their hypotheses that “the integration of palliative care with standard oncologic care may facilitate the optimal and appropriate administration of anticancer therapy, especially during the final months of life” and earlier referral to a hospice program may result in “better management of symptoms, leading to stabilization of [the patient’s] condition and prolonged survival.”

In practice, this study and those that followed have further spurred the integration of palliative care into many standard outpatient oncology workflows, including features such as co-located palliative care teams and palliative-focused checklists/algorithms for primary oncology providers. Of note, in the inpatient setting, a recent meta-analysis concluded that early hospital palliative care consultation was associated with a $3200 reduction in direct hospital costs ($4250 in subgroup of patients with cancer).

Further Reading/References:
1. ClinicalTrials.gov
2. Wiki Journal Club
3. Profile of first author Dr. Temel
4. “Economics of Palliative Care for Hospitalized Adults with Serious Illness: A Meta-analysis” JAMA Internal Medicine (2018)
5. UpToDate, “Benefits, services, and models of subspecialty palliative care”

Summary by Duncan F. Moore, MD

Week 35 – PLCO

“Mortality Results from a Randomized Prostate-Cancer Screening Trial”

by the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial project team

N Engl J Med. 2009 Mar 26;360(13):1310-9. [free full text]

The use of prostate-specific-antigen (PSA) testing to screen for prostate cancer has been a contentious subject for decades. Prior to the 2009 PLCO trial, there were no high-quality prospective studies of the potential benefit of PSA testing.

Population: men ages 55-74 enrolled at 10 US academic centers

exclusion criteria – hx of prostate, lung, or colorectal cancer, current cancer tx, and > 1 PSA test in past 3 years

Intervention: annual PSA testing for 6 years with annual digital rectal exam (DRE) for 4 years

Comparison: usual care

Outcome:
Primary – prostate-cancer-attributable death rate
Secondary – incidence of prostate cancer

Subgroup analyses of primary outcome:

  • patients with no more than 1 PSA test prior to enrollment
  • patients with 2+ PSA tests prior to enrollment

Results:
38,343 patients were randomized to the screening group, and 38,350 were randomized to the usual-care group. Baseline characteristics were similar in both groups. Median follow-up duration was 11.5 years. Patients in the screening group were 85% compliant with PSA testing and 86% compliant with DRE. In the usual-care group, 40% of patients received a PSA test within the first year, and 52% received a PSA test by the sixth year. Cumulative DRE rates in the control group were between 40-50%.

By seven years, there was no significant difference in rates of death attributable to prostate cancer. There were 50 deaths in the screening group and only 44 in the usual-care group (rate ratio 1.13, 95% CI 0.75 – 1.70). At ten years, there were 92 and 82 deaths in the respective groups (rate ratio 1.11, 95% CI 0.83–1.50).

By seven years, there was a higher rate of prostate cancer detection in the screening group. 2820 patients were diagnosed in the screening group, but only 2322 were diagnosed in the usual-care group (rate ratio 1.22, 95% CI 1.16–1.29). By ten years, there were 3452 and 2974 diagnoses in the respective groups (rate ratio 1.17, 95% CI 1.11–1.22).

Treatment-related complications (e.g. infection, incontinence, impotence) were not reported in this study.

Implication/Discussion:
Yearly PSA screening increased the prostate cancer diagnosis rate but did not impact prostate-cancer mortality when compared to the standard of care.

However, there were relatively high rates of PSA testing in the usual-care group (40-50%). The authors cite this finding as a probable major contributor to the lack of mortality difference. Other factors that may have biased to a null result were prior PSA testing and advances in treatments for prostate cancer during the trial. Regarding the former, 44% of men in both groups had already had one or more PSA tests prior to study enrollment. Prior PSA testing likely contributed to selection bias.

PSA screening recommendations prior to this 2009 study:

  • American Urological Association and American Cancer Society – recommended annual PSA and DRE, starting at age 50 if normal risk and earlier in high-risk men
  • National Comprehensive Cancer Network: “a risk-based screening algorithm, including family history, race, and age”
  • 2008 USPSTF Guidelines: insufficient evidence to determine balance between risks/benefits of PSA testing in men younger than 75; recommended against screening in age 75+ (Grade I Recommendation)

The authors of this study conclude that their results “support the validity of the recent [2008] recommendations of the USPSTF, especially against screening all men over the age of 75.”

However, the conclusions of the European Randomized Study of Screening for Prostate Cancer (ERSPC), which was published concurrently with PLCO in NEJM, differed. In ERSPC, PSA was screened every 4 years. The authors found an increased rate of detection of prostate cancer, but, more importantly, they found that screening decreased prostate cancer mortality (adjusted rate ratio 0.80, 95% CI 0.65–0.98, p = 0.04; NNT 1410 men receiving 1.7 screening visits over 9 years). Like PLCO, this study did not report treatment harms that may have been associated with overly zealous diagnosis.

The USPSTF reexamined its PSA guidelines in 2012. Given the lack of mortality benefit in PLCO, the pitiful mortality benefit in ERSPC, and the assumed harm from over-diagnosis and excessive intervention in patients who would ultimately not succumb to prostate cancer, the USPSTF concluded that PSA-based screening for prostate cancer should not be offered (Grade D Recommendation).

However, this guideline is under active consideration as of March 2018. See https://screeningforprostatecancer.org/. The draft recommendations encourage men ages 55-69 to have an informed discussion with their physician about potential benefits and harms of PSA-based screening (Grade C Recommendation). The USPSTF continues to recommend against screening in patients over 70 years old.

Screening for prostate cancer remains a complex and controversial topic. While we await further guidelines, we should continue to provide our patients with the aforementioned informed discussion. UpToDate has a nice summary of talking points culled from several sources.

Further Reading/References:
1. 2 Minute Medicine
2. ERSPC @ Wiki Journal Club
3. UpToDate, Screening for Prostate Cancer

Summary by Duncan F. Moore, MD

Week 25 – CLOT

“Low-Molecular-Weight Heparin versus a Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer”

by the Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators

N Engl J Med. 2003 Jul 10;349(2):146-53. [free full text]

Malignancy is a pro-thrombotic state, and patients with cancer are at significant and sustained risk of venous thromboembolism (VTE) even when treated with warfarin. Warfarin is a suboptimal drug that requires careful monitoring, and its effective administration is challenging in the setting of cancer-associated difficulties with oral intake, end-organ dysfunction, and drug interactions. The 2003 CLOT trial was designed to evaluate whether treatment with low-molecular-weight heparin (LMWH) was superior to a vitamin K antagonist (VKA) in the prevention of recurrent VTE.

Population: adults with active cancer and newly diagnosed symptomatic DVT or PE

The cancer must have been diagnosed or treated within past 6 months, or the patient must have recurrent or metastatic disease.

Intervention: dalteparin subQ daily (200 IU/kg daily x1 month, then 150 IU/kg daily x5 months)

Comparison: vitamin K antagonist x6 months (with 5-7 day LMWH bridge), target INR 2.5

Outcomes:

primary = recurrence of symptomatic DVT or PE within 6 months follow-up

secondary = major bleeding, any bleeding, all-cause mortality

 

Results:
338 patients were randomized to the LMWH group, and 338 were randomized to the VKA group. Baseline characteristics were similar among the two groups. 90% of patients had solid malignancies, and 67% of patients had metastatic disease. Within the VKA group, INR was estimated to be therapeutic 46% of the time, subtherapeutic 30% of the time, and supratherapeutic 24% of the time.

Within the six-month follow-up period, symptomatic VTE occurred in 8.0% of the dalteparin group and 15.8% of the VKA group (HR 0.48, 95% CI 0.30-0.77, p=0.002; NNT = 12.9). The Kaplan-Meier estimate of recurrent VTE at 6 months was 9% in the dalteparin group and 17% in the VKA group.

6% of the dalteparin group developed major bleeding versus 6% of the VKA group (p = 0.27). 14% of the dalteparin group sustained any type of bleeding event versus 19% of the VKA group (p = 0.09). Mortality at 6 months was 39% in the dalteparin group versus 41% in the VKA group (p = 0.53).

Implication/Discussion:
Treatment of VTE in cancer patients with low-molecular-weight heparin reduced the incidence of recurrent VTE relative to the incidence following treatment with vitamin K antagonists.

Notably, this reduction in VTE recurrence was not associated with a change in bleeding risk. However, it also did not correlate with a mortality benefit either.

This trial initiated a paradigm shift in the treatment of VTE in cancer. LMWH became the standard of care, although access and adherence to this treatment was thought to be limited by cost and convenience.

Until last week, no trial had directly compared a DOAC to LMWH in the prevention of recurrent VTE in malignancy. In an open-label, noninferiority trial, the Hokusai VTE Cancer Investigators demonstrated that the oral Xa inhibitor edoxaban (Savaysa) was noninferior to dalteparin with respect to a composite outcome of recurrent VTE or major bleeding.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Treatment of venous thromboembolism in patients with malignancy”
4. “Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism,” NEJM 2017

Summary by Duncan F. Moore, MD

Week 12 – Early Palliative Care in NSCLC

“Early Palliative Care for Patients with Metastatic Non-Small-Cell Lung Cancer”

N Engl J Med. 2010 Aug 19;363(8):733-42 [free full text]

Ideally, palliative care improves a patient’s quality of life while facilitating appropriate usage of healthcare resources. However, initiating palliative care late in a disease course or in the inpatient setting may limit these beneficial effects. This 2010 study by Temel et al. sought to demonstrate benefits of early integrated palliative care on patient-reported quality of life outcomes and resource utilization.

Population: outpatients with metastatic NSCLC diagnosed < 8 weeks ago and ECOG performance status 0-2

Intervention: “early palliative care” – met with palliative MD/ARNP within 3 weeks of enrollment and at least monthly afterward

Comparison: standard oncologic care

Outcome:

Primary – change in Trial Outcome Index (TOI) from baseline to 12 weeks

TOI = sum of the lung-cancer, physical well-being, and functional well-being subscales of the Functional Assessment of Cancer Therapy­–Lung (FACT-L) scale (scale range 0-84, higher score = better function)

Secondary

  • change in FACT-L score at 12 weeks (scale range 0-136)
  • change in lung-cancer subscale of FACT-L at 12 weeks (scale range 0-28)
  • “aggressive care,” meaning one of the following: chemo within 14 days before death, lack of hospice care, or admission to hospice ≤ 3 days before death
  • documentation of resuscitation preference in outpatient records
  • prevalence of depression at 12 weeks per HADS and PHQ-9
  • median survival

Results:
151 patients were randomized. There were no significant difference in baseline characteristics among the two groups. Palliative-care patients (n=77) had a mean TOI increase of 2.3 points, versus a 2.3-point decrease in the standard-care group (n=73) (p=0.04).

Secondary outcomes:

  • ∆ FACT-L score at 12 weeks: +4.2± 13.8 in the palliative group vs. -0.4 ±13.8 in the standard group (p=0.09 for difference between the two groups)
  • ∆ lung-cancer subscale at 12 weeks: +0.8±3.6 in palliative vs. +0.3±4.0 in standard (p=0.50)
  • aggressive end-of-life care was received in 33% of palliative patients vs. 53% of standard patients (p=0.05)
  • resuscitation preferences were documented in 53% of palliative patients vs. 28% of standard patients (p=0.05)
  • depression at 12 weeks per PHQ-9 was 4% in palliative patients vs. 17% in standard patients (p = 0.04)
  • median survival was 11.6 months in the palliative group versus 8.9 months in the standard group (p=0.02). (See Figure 3 on page 741 for the Kaplan-Meier curve.)

Implication/Discussion:
Early palliative care in patients with metastatic non-small cell lung cancer improved quality of life and mood, decreased aggressive end-of-life care, and improved survival.

This is a landmark study, both for its quantification of the quality-of-life (QoL) benefits of palliative intervention and for its seemingly counterintuitive finding that early palliative care actually improved survival.

The authors hypothesized that the demonstrated QoL and mood improvements may have led to the increased survival, as prior studies had associated lower QoL and depressed mood with decreased survival. However, I find more compelling their hypotheses that “the integration of palliative care with standard oncologic care may facilitate the optimal and appropriate administration of anticancer therapy, especially during the final months of life” and earlier referral to a hospice program may result in “better management of symptoms, leading to stabilization of [the patient’s] condition and prolonged survival.”

In practice, this study and those that followed have further spurred the integration of palliative care into many standard outpatient oncology workflows, including features such as co-located palliative care teams and palliative-focused checklists/algorithms for primary oncology providers.

Limitations of this study: 1) a complex subjective primary endpoint, 2) non-blinded, 3) single-center, minimally diverse patient population.

Further Reading/References:
1. ClinicalTrials.gov
2. Wiki Journal Club
3. Profile of first author Dr. Temel
4. UpToDate, “Benefits, services, and models of subspecialty palliative care”

Summary by Duncan F. Moore, MD

Week 4 – NLST

“Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening”

by the National Lung Cancer Screening Trial Research Team

N Engl J Med. 2011 Aug 4;365(5):395-409 [NEJM free full text]

Despite a reduction in smoking rates in the United States, lung cancer remains the number one cause of cancer death in the United States, as well as worldwide. Earlier studies of plain chest radiograph for lung cancer screening demonstrated no benefit, and thus in 2002 the National Lung Screening Trial (NLST) was undertaken to determine whether then-recent advances in CT technology could lead to an effective lung cancer screening method.

Population: adults age 55-74 with 30+ pack-years of smoking (if former smokers, they must have quit within the past 15 years)
Intervention: three annual screenings for lung cancer with low-dose CT
Comparison: three annual screenings for lung cancer with PA chest radiograph
Outcome: 1º = mortality from lung cancer, 2º = mortality from any cause and incidence of lung cancer

Results/Conclusion:
53,454 patients were randomized, and both groups had similar baseline characteristics. The low-dose CT group demonstrated 247 deaths from lung cancer per 100,000 person-years, whereas the radiography group demonstrated 309 deaths per 100,000 person-years. Thus a relative reduction in rate of death by 20.0% was seen in the CT group (95% CI 6.8 – 26.7%, p = 0.004). The number needed to screen with CT to prevent one lung cancer death was 320. There were 1877 deaths from any cause in the CT group and 2000 deaths in the radiography group; thus CT screening demonstrated a risk reduction of death from any cause of 6.7% (95% CI 1.2% – 13.6%, p = 0.02). Incidence of lung cancer in the CT group was 645 per 100,000 person-years and 941 per 100,000 person-years in the radiography group (RR 1.13, 95% CI 1.03 – 1.23).

Implication/Discussion:
Lung cancer screening with low-dose CT scan in high-risk patients provides a significant mortality benefit.

This trial was stopped early because the mortality benefit was so high. The benefit was driven by the reduction in deaths attributed to lung cancer – and when deaths from lung cancer were excluded from the overall mortality analysis there was no significant difference among the two arms. Largely on the basis of this study, the 2013 USPSTF guidelines for lung cancer screening recommend annual low-dose CT scan in patients who meet NLST inclusion criteria.

Per UpToDate, there are seven low-dose CT screening trials in progress in Europe. It is hoped that meta-analysis of all such RCTs will allow for further refinement in risk stratification, frequency of screening, and management of positive screening findings.

Of note, no randomized trial has ever demonstrated a mortality benefit of chest radiography for lung cancer screening. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial tested this modality vs. “community care,” and because the PLCO trial was ongoing at the time of creation of the NSLT, the NSLT authors trial decided to compare their intervention (CT) to chest radiography, in case the results of chest radiography in PLCO were positive (ultimately they were not).

Further Reading:
1. USPSTF Guidelines for Lung Cancer Screening (2013)
2. ClinicalTrials.gov
3. Wiki Journal Club
4. 2 Minute Medicine

Summary by Duncan F. Moore, MD