Special Populations in Lung Cancer Explored

Rogerio C. Lilenbaum, MD

During the past year, a new treatment paradigm has been validated for patients with advanced non-small cell lung cancer (NSCLC) and performance status 2 (PS2) who traditionally have been considered a “special population” unlikely to benefit from chemotherapy.

Yet accurately assessing patients’ performance status remains a challenge. And, some leading oncologists argue, it is time to stop labeling as “special” a group of patients who do have treatment options and who constitute a large proportion of those diagnosed with advanced disease.

Those were among the points that Rogerio C. Lilenbaum, MD, made during a presentation at the 7th Annual New York Lung Cancer Symposium November 10 in New York City, a one-day gathering hosted by Physicians’ Education Resource.

Lilenbaum has been studying therapies for patients classified as “special populations,” including the elderly and those with PS2 status, for more than a decade. As a thoracic oncologist in Miami Beach, Florida, Lilenbaum led a groundbreaking clinical trial that established the chemotherapy doublet of carboplatin and pemetrexed (Alimta) as an effective and superior treatment regimen for patients with PS2 status.

Lilenbaum has served since 2011 as chair of the Cancer Institute at the Cleveland Clinic in Weston, Florida, and previously worked as director of the Thoracic Oncology Program at Mount Sinai Medical Center in Miami Beach.

In January, Lilenbaum is scheduled to become chief medical officer of the Smilow Cancer Hospital at Yale- New Haven in Connecticut.

Lilenbaum began his presentation at the PER symposium by stressing the proportion of patients assessed as PS2.

Assessing PS2

“This is a heterogeneous group of patients,” said Lilenbaum. “A lot of different people fall into this designation of performance status 2. It is, however, a pretty significant percentage of our practice, at least 30%, if not 40% in some studies, depending on where they come from⎯if it’s ambulatory versus hospital, if it’s all lung cancer versus non-small cell. But it’s not an insignificant component of anybody’s practice for people who deal with lung cancer.”An underlying question concerning research studies and management of patients with PS2 is whether they have been accurately assessed. Under the Eastern Cooperative Oncology Group (ECOG) scale, a PS2 patient is defined as one who is “ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours.”¹

“We’re not very good at assessing performance status,” said Lilenbaum. “Even though a scale has been available and has been widely known for over three to four decades, we don’t always utilize that scale very well in clinical practice.”

He noted, for example, that PS2 patients could be misclassified as either PS1 or PS3 in practice and research. “What is really a performance status 2 patient? They’re not the patients who come in on a stretcher, those who come in with the oxygen tank, and are wheelchairbound, and can’t really get up from the chair to the exam table. Those are not performance status 2 patients, and that’s a misconception that we’ve all had to deal with for a long time. These individuals are ambulatory. They’re capable of all self-care. They just can’t work. That’s the difference between PS2 and PS1,” Lilenbaum said.

Lilenbaum said there is a need for a formal instrument that results in a quantifiable metric with a reproducible result. He said that, beyond the traditional ECOG criteria, he uses an abbreviated form of a geriatric assessment test.

Mark G. Kris, MD

Mark G. Kris, MD, chief of the Thoracic Oncology Service at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City and a program director of the PER symposium, said the clinical assessment of a patient’s performance status should be detailed.

“You have to ask the questions that tell you how to determine performance status,” he said in an interview. “You have to ask, ‘Can you go to work? What activities can you do at home or can’t do?’ You have to specifically ask those questions. You cannot estimate it. And that’s the key thing. You have to read a performance status card or list or however you have it and ask the patient those questions.”

Kris said he also uses the simpler “Get Up and Go” test, in which a patient is asked to walk 10 feet, turn around, and sit down again.

Hints of Strategies for PS2 Patients

Treatment of PS2 patients has always been a thorny question, he noted. “PS2 was a middle ground, and it was always a case where people spent a lot of soul searching whether treatment was the right thing or not,” said Kris.In the early 1980s, patients classified as PS2 demonstrated such poor outcomes to the chemotherapy cocktails then given to patients with advanced lung cancer that researchers believed they should be excluded from phase III clinical trials.² “This became dogma, and it sort of permeated the field for over a decade,” Lilenbaum said.

A decade later, ECOG revisited the matter in the ECOG 1594 trial, which evaluated four different chemotherapy regimens. Although 6% of the 1155 participants with stage IIIB/IV lung cancer were patients with PS2 status, enrollment was halted for those assessed at this level because they were doing so poorly, Lilenbaum said.^3,4 He said it is unclear whether the disease or the treatment, or a mixture of both, was responsible for the dismal outcome.

The picture began to change, however, in the 2000s. In a retrospective analysis of two phase III STELLAR trials involving nearly 800 patients with NSCLC classified as PS2, Lilenbaum and colleagues examined outcomes to the chemotherapy regimens by risk factors of prognostic significance commonly used for PS1 patients: albumin (<3.5−≥3.5), extrathoracic disease, lactate dehydrogenase levels (≥200−<200), and the number of comorbidities (>2−≤2).⁵

They found PS2 patients with none of the risk factors who had the same outcomes as would have been expected in patients classified as PS0-PS1.

Lilenbaum then led Cancer And Leukemia Group B (CALGB) trial 9730, the group’s first trial that included PS2 as a stratification factor.⁶ “The only reason that was done was because that trial was a single agent versus a doublet trial. This was carboplatin/paclitaxel versus paclitaxel alone, and because of that, we felt that it was ‘safe’ to include performance status 2 patients,” Lilenbaum said.

Doublet Regimen Proves Effective

Figure. Design of Chemotherapy Trial

Eligibility

• Stage IIIB/IV NSCLC (malignant effusion)
• ECOG PS2
• No prior chemotherapy
• Stable CNS disease
• Measurable disease
• Adequate organ function (including GFR ≥45 mL/min)

Randomization 1:1

Stratification factors:

• Stage: IIIB vs IV
• Age: ≥70 vs <70
• Wt loss: ≥5% vs <5%

Arm A

Pemetrexed

500 mg/m2 IV Q3W

Pemetrexed 500 mg/m2 IV Q3W

+

Carboplatin AUC 5 IV Q3W

Arm B

x 4 cycles

AUC indicates area under the curve; CNS, central nervous system; ECOG, Eastern Cooperative Oncology Group; GFR, glomerular filtration rate; IV, intravenous; NSCLC, non-small cell lung cancer; PS, performance status; Wt, weight.

Lilenbaum R. Establishing a standard of care for PS2 patients with advanced NSCLC> Presented at: 7th Annual New York Lung Cancer Symposium; November 10, 2012; New York, NY

“Surprisingly, performance status 2 patients benefited from the combination compared to the single agent. If anything, one thing that most people don’t realize about this trial is that if you exclude performance status 2 patients and you only look at the 0 to 1’s, the difference between single-agent and combination chemotherapy is no longer significant. So it was an interesting trial that raised a lot of questions, and it basically said, well, if we can deliver the treatment and we can do it safely, the sicker patients are the ones that need the more aggressive treatment.”Taking another step to define treatment for this patient population, Lilenbaum and colleagues designed a phase III randomized trial to evaluate pemetrexed versus carboplatin plus pemetrexed in PS2 patients with stage III/IV NSCLC (Figure ).

The trial was conducted largely in Brazil, where Lilenbaum attended medical school, and at his former institution in Miami Beach. The study, which began enrolling patients in April 2008, was designed before the advent of several research advances in lung cancer, including maintenance therapy. (Alimta, initially approved in 2004, is indicated for the treatment of locally advanced or metastatic nonsquamous NSCLC in several settings.)

In presenting the study results at the American Association of Clinical Oncology Annual Meeting (ASCO) in June,⁷ Lilenbaum said one of the major objectives of the study was “to give us a definitive answer to what we considered an important gap in our knowledge” of the optimal chemotherapy regimen for PS2 patients.

He also said there had never before been a randomized, phase III, multicenter, investigator-initiated trial in Brazil or any Latin American country for patients with lung cancer. “The challenges of mounting such a research infrastructure in Brazil were as huge as the country itself, with eight centers, some of them more than 2000 miles apart,” Lilenbaum told the ASCO attendees.

At the PER conference, Lilenbaum said researchers at the central institution conducting the trial in Brazil took care to ensure that they recruited patients who truly were PS2. “The patient could not go on trial unless two investigators agreed on the designation of performance status 2. There were a lot of patients who ended up being excluded because of that. So we were really confident that this is a reasonable PS2 population,” he said.

Table 1. PS2 Patients in Chemotherapy Trial

Pemetrexed

(n = 102)

Pemetrexed +

Carboplatin

(n = 103)

Age (years)

Median (range)

≥70 y (%)

65 (40-86)

35.3

65 (41-90)

36.8

Sex (%)

Male

Female

58.8

41.2

63.1

36.9

Stage (%)

IIIB

IV

4.9

95.1

5.8

94.2

Smoking Status (%)

Current

Former

Never

10.8

66.7

22.5

17.5

60.2

22.3

Comorbidities (%)

Hypertension

COPD

Diabetes mellitus

45.1

17.6

7.8

44.7

11.7

12.6

COPD indicates chronic obstructive pulmonary disease.

Lilenbaum R. Establishing a standard of care for PS2 patients with advanced NSCLC. Presented at: 7th Annual New York Lung Cancer Symposium; November 10, 2012; New York, NY.

He also noted that enrolled patients did not have a high number of comorbidities (Table 1). In the area of histology, approximately 80% of the participants had adenocarcinomas; Lilenbaum said the trial initially enrolled people with squamous cell carcinomas, but such patients later were excluded.

The differences in outcomes between the two regimens were dramatic (Table 2 on Next Page). At 12 months, the overall survival (OS) rate, the primary endpoint of the trial, among patients who took the chemotherapy doublet was 43% versus 18% for single-agent therapy. The progression- free survival (PFS) rate at 12 months was 18% in the doublet arm compared with 4% in the single-agent arm.

Lilenbaum said toxicity “was relatively mild in both arms.” The incidence of grade 3/4 events among patients in the pemetrexed versus carboplatin/pemetrexed arms included anemia (3.9% vs 11.7%, respectively); neutropenia (1% vs 5.8%); febrile neutropenia (2.9% vs 1.9%); and dyspnea (10.8% vs 5.8%). There were four deaths in the doublet arm, which were attributed to renal failure, sepsis, pneumonia, and thrombocytopenia.

In his ASCO presentation, Lilenbaum said the results of the clinical trial could be applied to PS2 patients regardless of histological subtypes. “Given the magnitude of the benefit, and the immediate applicability of these data to clinical practice, we urge organizations to revise their guidelines,” he said.

In further discussion at the PER conference, Lilenbaum noted that clinicians also should consider adjusting doses for patients to improve outcomes. “Dose manipulations, especially dose adjustments, are one of the most underutilized weapons that we have,” he said. “It can make a huge difference.”

Table 2. Key Statistics in PS2

Chemotherapy Trial

Pemetrexed

Pemetrexed +

Carboplatin

Overall survival

Median, mo

At 6 mo, %

At 12 mo, %

5.6

50

18

9.1

65

43

HR; P value

HR = 0.57; P = .001

Progression-free survival

Median, mo

At 6 mo, %

At 12 mo, %

3.0

17

4

5.9

47

18

HR; P value

HR = 0.46; P < .001

HR indicates hazard ratio.

Lilenbaum R. Establishing a standard of care for PS2 patients with advanced NSCLC. Presented at: 7th Annual New York Lung Cancer Symposium; November 10, 2012; New York, NY.

Potential for Targeted Therapies

With the advent of tyrosine kinase inhibitors, researchers have explored whether treatment with erlotinib (Tarceva) is an option for patients with poor performance status who are not candidates for chemotherapy and whose only other choice would be best supportive care. (Tarceva is approved as maintenance therapy and after prior chemotherapy in locally advanced or metastatic NSCLC.)

The TOPICAL trial evaluated erlotinib (150 mg/d) compared with placebo in patients with stage IIIB/IV NSCLC who were PS2-PS3 or PS0-PS1 with impaired renal function. In results reported in November, the median OS was not improved for the 350 patients who received erlotinib (3.7 months; 95% CI, 3.2−4.2 months), compared with the 320 participants on placebo (3.6 months; 95% CI, 3.2−3.9 months).⁸ However, patients who received erlotinib and experienced a first-cycle rash achieved a higher OS (HR = 0.76; 95% CI, 0.63−0.92; P = .0058), compared with those who took the placebo.

Lee et al concluded that patients with NSCLC who are “deemed unsuitable to chemotherapy could be given erlotinib,” but that the drug should be discontinued after 28 days if they do not develop a rash.

Lilenbaum noted that data from the TOPICAL study presented earlier at an ASCO meeting indicated a benefit for female patients in both OS and PFS.⁹

“Erlotinib is best used in patients selected by molecular criteria but may be considered in female patients with adenocarcinoma whose alternative is supportive care,” Lilenbaum concluded.

Looking forward, Lilenbaum noted that the ToPPS trial will evaluate whether bevacizumab (Avastin) improves PFS, either when added to pemetrexed or carboplatin/ pemetrexed compared with pemetrexed alone in chemotherapy-naïve patients with stage IIIB NSCLC and PS2 status.¹⁰ (Avastin is approved for patients with advanced nonsquamous NSCLC in combination with carboplatin and paclitaxel who have not received chemotherapy for their advanced disease.)

Terminology Revision Suggested

Lilenbaum is chairing the study, which is sponsored by the Sarah Cannon Research Institute in Nashville, Tennessee.As therapies for patients with NSCLC advance, does it make sense to consider patients with PS2 status a “special population”?

In his ASCO presentation earlier this year, Lilenbaum suggested that evolving treatment regimens render the term moot. “We have finally closed that loop for PS2 patients,” Lilenbaum said. “I do believe that the designation of ‘special populations’ no longer applies.”

Kris, in the interview, said the term conflicts with the concept of personalizing therapy for each patient. “Of course you’re going to have a different treatment for a person who is in a wheelchair with stage IV cancer than a person who is at work with a stage IV cancer. So which one is the special population? They’re both special,” he said. “It’s the same thinking though for all those patients⎯choosing the best therapy for the biology and the physiology of that patient.”

References

1. ECOG performance status. Eastern Cooperative Oncology Group website. http://www.ecog.org/general/perf_stat.html. Updated July 27, 2008. Accessed December 3, 2012.
2. Ruckdeschel JC, Finkelstein DM, Ettinger DS, et al. A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol. 1986;4(1):14-22.
3. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2):92-98.
4. Sweeney CJ, Zhu J, Sandler AB, et al. Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a phase II trial in patients with metastatic non-small cell lung carcinoma. Cancer. 2001; 92(10):2639-2647.
5. Lilenbaum R, Villaflor V, Langer C, et al. Single-agent versus combination chemotherapy in patients with advanced non-small cell lung cancer and a performance status of 2: prognostic factors and treatment selection based on two large randomized clinical trials. J Thorac Oncol. 2009;4(7):869-874.
6. Lilenbaum RC, Herndon JE, List MA, et al. Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the Cancer And Leukemia Group B (study 9730). J Clin Oncol. 2005;23(1):190-196.
7. Lilenbaum R, Zukin M, Pereira JR, et al. A randomized phase III trial of single-agent pemetrexed (P) versus carboplatin and pemetrexed (CP) in patients with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2. Presented at: American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago, IL. Abstract 7506.
8. Lee SM, Khan I, Upadhyay S, et al. First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial [Published online ahead of print October 16, 2012]. Lancet Oncol. 2012;13(11):1161- 1170. doi:10.1016/S1470-2045(12)70412-6.
9. Lee S, Rudd R, Khan I, et al. TOPICAL: randomized phase III trial of erlotinib compared with placebo in chemotherapy-naive patients with advanced non-small cell lung cancer (NSCLC) and unsuitable for first-line chemotherapy. J Clin Oncol. 2010;28:15(suppl; abstr 7504).
10. US National Institutes of Health. Trial of poor performance status patients (ToPPS) (NCT00892710). ClinicalTrials.gov website. www.clinicaltrials.gov. Updated September 28, 2012. Accessed December 5, 2012