Management of Patients With Lung Cancer and Poor Performance Status

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All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/49339; and 4) view/print certificate.

Release date: July 8, 2014; Expiration date: July 8, 2015

Learning Objectives

Upon completion of this activity, participants will be able to:

• Describe the available evidence on the treatment of patients with lung cancer who are considered to have poor PS

• Explain alternative treatment options for those patients with comorbidities or poor PS

The median age at diagnosis of lung cancer in the United States is approximately 70 years.¹ As a result, a significant proportion of patients with lung cancer will have intercurrent illnesses or comorbid conditions that can potentially affect their ability to receive standard therapy for lung cancer. Individuals with poor or borderline functional status account for a significant proportion of all patients with lung cancer. In an analysis of data from 2885 patients, 503 of whom had lung cancer, the prevalence of poor performance status (PS) was 34% based on provider assessments, but was actually higher when estimated by the patients (48%). These data show that the incidence of poor PS is high among patients with all stages of lung cancer.²

Two major scoring systems that help estimate a person's ability to perform daily activities are routinely used to determine a patient's PS: the ECOG scale³ and the Karnofsky Performance Scale (KPS).⁴ Patients who are able to care for themselves but are unable to perform most work-related activities (ie, ECOG ≥2 or KPS ≤70%) are considered to have a poor PS. Two major subsets of patients can be included in this group: those who were in poor health and develop lung cancer, and those who were in good health before developing lung cancer whose current PS is a result of their malignancy. Because most trials do not distinguish between these groups, whether they are physiologically the same is unclear.

Current evidence suggests that patients with lung cancer with a poor PS, irrespective of age, have an increased incidence of adverse effects with standard chemotherapy and have a poorer overall survival (OS).^5,6 Hence, these individuals form a select subgroup of patients with lung cancer who need to be treated differently. Unfortunately, these individuals are underrepresented in conventional clinical trials because of enrollment restrictions based on normal or near-normal organ function. Moreover, clinical trials of special populations of patients with lung cancer tend to include older patients and those with a poor PS together, even though these are vastly different patient populations that respond differently to treatment and have different outcomes.⁷

Another challenge in interpreting the trial evidence for this group of patients is the subjectivity associated with assigning a PS to any given patient. A recent study evaluating carboplatin and 1 of 2 paclitaxel formulations in treatment-naïve patients with advanced non-small cell lung cancer (NSCLC) and a marginal PS found a significant difference in OS based on the geographic location of the patients.⁸ Because all of the factors were identical, the only possible explanation for this discrepancy, although unproven, is that the criteria vary for the assignment of PS 2.⁸ Lending further credence to this is the finding that patients with PS 2 enrolled into large trials that did not limit eligibility based on PS seem to have worse outcomes compared with patients with PS 2 enrolled in trials specifically designed for patients with PS 2 using the same chemotherapy regimens.⁹ For example, patients with PS 2 in the CALGB 9730 trial¹⁰ (which enrolled patients with PS 0-2) had a median OS of 4.7 months with the carboplatin-paclitaxel doublet. In contrast, in another trial led by the same investigators specifically designed for patients with PS 2, the median OS with the same combination was 9.7 months.¹¹ Despite taking into account the fallacies associated with intertrial comparisons, these observations suggest that a wide variation exists in the criteria used to label patients as having PS 2. Hence, any interpretation of data in these patients will need to take this subjectivity into account. This article attempts to summarize the evidence for the treatment of patients with lung cancer and a poor PS.

Early Stage

Limited data are available on the management of patients with poor PS with early-stage NSCLC. When comorbidities or poor PS exclude surgical interventions for early-stage lung cancer, radiation therapy is the standard alternative.

Role of Surgery

Much of the data on outcomes stratified by PS come from literature on elderly patients. In a retrospective analysis of 367 patients with lung cancer conducted in the United Kingdom, patients 75 years of age and older were significantly more likely to have a PS of 2 to 4 than those younger than 75 years (70.9% vs 33.8%; P<.001). Older patients also were less likely to receive active treatment and have a poorer OS (8.5 vs 2.4 months; P<.001).¹² Although the trial focused on differences among older and younger patients, when the 2 age groups were considered separately, survival remained improved in patients with PS 0 to 1 (hazard ratio [HR], 1.88; (P<.001), suggesting that patients with poor PS do worse with surgery. Similar findings were noted in a small Japanese study that evaluated risk factors for postoperative death after lung cancer surgery in patients with poor pulmonary reserves (forced expiratory volume in the first second of expiration <1 L).¹³ In this analysis, a PS of 2 or greater was associated with an increased risk of death (44.4% vs 9.5%; P=.005). In a large retrospective study that examined outcomes of 3082 patients with pathologic stage IA NSCLC diagnosed between 1982 and 1997, disease-specific survival and OS rates at 10 years were worse in patients with PS 1 or greater compared with patients with PS 0 (62.0% vs 69.9%; P<.0001, and 41.8 vs 58.1; P<.0001, respectively).¹⁴

Patients with severely compromised lung function are often denied surgical resection, because a lobectomy can affect their lung function even further. A recent retrospective analysis of 50 patients who had a predicted postoperative diffusing capacity of carbon monoxide of 40% or less and underwent a lobectomy found no operative complications and a median hospital stay of 5 days.¹⁵ The 5-year OS rate for this cohort was 69%. The presence of diabetes predicted for worse mortality and oxygen dependence postoperatively. The authors concluded that a lobectomy was feasible even in individuals with poor lung function.

In an effort to decrease the morbidity and mortality, limited lung resection was attempted. Only one prospective randomized trial published to date has compared lobectomy with a more limited resection.¹⁶ In this trial, patients undergoing limited resection had significant increases in recurrence rates (0.10 vs 0.06 per person per year; P=.02) and higher death rates from lung cancer (0.07 vs 0.05 per person per year; P=.094). Small single-institution retrospective studies have shown that patients who are medically unfit to undergo a lobectomy can be treated with limited resection and experience clinically meaningful survival.^17,18

In a meta-analysis that compared lobectomy with limited resection, no significant survival difference was noted between the approaches.¹⁹ However, the results should be interpreted with caution, given the heterogeneity between the studies included in this analysis. A SEER database analysis found that although lobectomy provided a survival benefit over limited resection in younger patients, both approaches produced similar survival in individuals older than 71 years.²⁰ One reason for this may be other competing causes of death that are more relevant in older patients, and this argument may also be valid for individuals with poor PS.

Role of Radiation: Patients presenting with inoperable disease because of comorbidities or poor PS are often treated with radiation therapy given in a definitive dosing fashion.²¹ In a large nationwide study of patterns of care, a larger proportion of patients who received definitive radiation as opposed to surgery had a KPS of 60 or 70 (20.9% vs 6.6%), although this did not reach statistical significance.²²

Even among patients treated with conventional radiation, PS seems to affect outcomes.²³ In a series of 62 patients with stage II NSCLC treated with conventional radiation therapy, patients with PS 0 to 1 had a better median OS than those with PS 2 to 3 (23 vs 6 months; P<.0001).²⁴ In another study of 116 patients with stages I and II NSCLC treated with hyperfractionated radiation therapy, PS was a predictor of OS, local progression-free survival (PFS), and distant metastases-free survival.²⁵ Patients with a KPS of 70 to 80 had worse OS, local PFS, and distant metastases-free survival than those with a KPS of 90 to 100 at 5 years (0 vs 42%; 0 vs 57%; 0 vs. 90%, respectively; P<.0001 for all comparisons).

Stereotactic ablative body radiation (SABR) uses higher doses per fraction but a lesser number of treatments. SABR is considered biologically more effective at killing cancer cells because of the higher dose per treatment. Multiple studies have provided the evidence for the role of SABR for NSCLC in medically inoperable candidates. Table 1 describes some of these trials.^26-34 Studies are currently evaluating the possibility of brachytherapy (ClinicalTrials.gov identifier: NCT01757158) and stereotactic radiation with or without brachytherapy (ClinicalTrials.gov identifier: NCT01336894) after limited resection in patients with marginal lung function who are not candidates for lobectomy.

Although the evidence is sparse, available data from one study suggest that PS does not affect outcomes after SABR. In a Danish study of 88 inoperable patients with early-stage NSCLC, patients with PS 0 to 1 had a similar median OS compared with those with PS 2 to 3 (29.0 vs 17.7 months; P=.115).³⁵ However, in this study, the age-adjusted Charlson comorbidity index, which is a weighted index that takes into account the number and seriousness of comorbid disease, was greater than 5 (relative risk, 2.14; 95% CI, 1.19-3.84; P=.011)³⁶ and was observed to be independently associated with inferior OS.

Table 1

Primary Tumor Control Results After Stereotactic Ablative Body Radiation of Stage I Non-Small Cell Lung Cancer

View Table

In summary, patients with early-stage disease and a marginal lung function should be evaluated in a multidisciplinary setting to determine suitability for limited resection or SABR. In the absence of randomized trials, whether one approach is superior to the other is unclear.

Adjuvant Chemotherapy: Data are sparse on the role of adjuvant chemotherapy in patients with PS 2 after surgical resection of patients with early-stage NSCLC. Of the modern trials that evaluated the role of adjuvant chemotherapy, only 2, IALT³⁷ and ANITA,³⁸ allowed enrollment of patients with PS 2. Approximately 7% of patients in the IALT study and 3% in the ANITA trial were PS 2, and hence no definite conclusion can be drawn regarding the utility of adjuvant therapy in this population. The LACE meta-analysis of all the recent adjuvant trials³⁹ showed the possibility that chemotherapy was detrimental to these patients, and concluded that these patients should probably not be offered adjuvant chemotherapy.

Locally Advanced Disease

Many treatment options using different modalities are available for the treatment of locally advanced NSCLC, but the optimal approach is still being identified. Published trials of combined modality therapy included patients with stages I-III disease, which hampers subset analyses because of the lack of statistical power. Concurrent chemotherapy and radiation offer better outcomes than sequential or single-modality therapy.^40-42 Almost 25% of patients included in RTOG 9410 had a KPS of 70 to 80.⁴² Although the effects of KPS on toxicity are not available in this study, patients with a poor PS had a significantly worse OS than those with a good PS (P=.007). In a CALGB study that evaluated the role of adding gefitinib to chemoradiotherapy, patients with poor PS had a worse response rate than good-risk patients (52.4% vs 81.6%; P=.033).⁴³ Despite this, however, and surprisingly, they had a better median PFS (13.4 vs 9.2 months) and OS (19.0 vs 13.0 months). The INT1039 study investigated the role of trimodality therapy in patients with T1-3pN2M0.⁴⁴ Approximately 12% of patients enrolled in this study had a KPS of 70 to 80. PS was not an independent risk factor for survival in this study. Thus, based on these conflicting results, the benefit of standard therapy in patients with poor PS and locally advanced disease is difficult to evaluate.

However, toxicity, especially myelosuppression and esophagitis, is higher with concurrent chemotherapy and radiation. Patients with poor PS are likely to have more chemotherapy-related complications secondary to myelosuppression, especially anemia and neutropenia.⁵ Hence, using sequential therapy may be prudent in this population, wherein radiation therapy follows the administration of systemic chemotherapy.

Advanced Disease

There is a dearth of literature clearly defining the management of patients with stage IV NSCLC and a PS 2, including issues such as treatment with single-agent versus combination and choice of specific agents, such as biologics. Current ASCO guidelines for chemotherapy in stage IV NSCLC state, “Available data support use of single-agent chemotherapy in patients with PS 2. Data are insufficient to make a recommendation for or against using a combination of 2 cytotoxic drugs in patients with a PS of 2.”⁴⁵

The following sections review the available evidence from the literature regarding the management of patients with PS 2. Results of phase III randomized studies and subset analyses specific to patients with PS 2 from phase III trials that permitted enrollment of patients with PS 2 are described. Table 2 provides a summary of the major studies.^{5,8,10,11,46-52}

Single-Agent Versus 2-Drug Combinations: Recent studies that have examined single agents versus 2-drug combinations for patients with PS 2 include 3 phase III trials with planned subgroup analyses by PS,^6,10,52 a phase II trial designed exclusively for patients with PS 2,⁵³ a phase II trial comparing traditional cytotoxic chemotherapy with erlotinib in patients with PS 2,¹¹ and a recently published phase III trial comparing carboplatin-based combination therapy to a single agent restricted to patients with PS 2.⁵¹

The subset analysis in CALGB 9730 (carboplatin-paclitaxel vs paclitaxel) revealed that patients with PS 2 had a significantly worse outcome than those with PS 0 to 1 (median survival, 3.0 vs 8.8 months; 1-year survival rate, 14% vs 38%, respectively). For patients with PS 2, the 1-year survival rate for combination chemotherapy was better than for single-agent therapy (18% vs 10%; HR, 0.60; P=.016). Rates of toxicities between the arms in both subgroups were comparable to those of the general study populations.¹⁰

In a trial that used non-platinum-based combination therapy, among the subset of patients with PS 2, no difference in median survival was seen between those who received single-agent docetaxel (n=57) and those who received a combination combination of docetaxel and gemcitabine (n=63; 2.9 vs 3.8 months, respectively; P=.62).⁴⁹ No survival differences were detected between the groups in the 223 patients with good PS (7.2 vs 8.0 months, respectively) either.

Quoix et al⁵² reported on a large, prospective, randomized, controlled trial limited to patients between 70 and 89 years of age that allowed those with PS 0 to 2. Patients received either 4 cycles (3 weeks on treatment, 1 week off) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15) or 5 cycles (2 weeks on treatment, 1 week off) of vinorelbine or gemcitabine monotherapy. Median OS was 10.3 months for doublet chemotherapy and 6.2 months for monotherapy (HR, 0.64; 95% CI, 0.52-0.78; P<.0001); 1-year survival rates were 44.5% (95% CI, 37.9-50.9) and 25.4% (95% CI, 19.9-31.3), respectively. Of the 451 patients enrolled in this study, 123 (27%) had PS 2. Although specific response rates and survival for this subgroup have not been reported, the HR of 0.63 (95% CI, 0.43-0.91) for patients with PS 2 in favor of the combination arm is virtually identical to that of patients with PS 0 to 1, suggesting that older patients with PS 2 derive more benefit from doublet chemotherapy, similar to older patients with good PS.

In a phase II trial comparing single-agent gemcitabine with the combination of gemcitabine and carboplatin, Kosmidis et al⁵³ reported that the median survival was 4.8 months (95% CI, 2.45-7.25) for the single agent compared with 6.7 months (95% CI, 2.47-10.8) for the combination (P=.49).

A recent large phase III clinical trial was the first to evaluate single versus doublet chemotherapy specifically in patients with PS 2 and metastatic NSCLC.⁵¹ This multicenter study randomized patients with metastatic NSCLC and ECOG PS 2 (initially inclusive of all NSCLC histologies, but later amended to restrict to adenocarcinomas only) to either pemetrexed alone or in combination with carboplatin for 4 planned cycles. A total of 205 eligible patients were enrolled from 8 centers in Brazil and 1 in the United States. The response rates were 10.3% for single-agent pemetrexed and 23.8% for the combination (P=.032). In the intent-to-treat population, combination therapy was associated with better median PFS (5.8 vs 2.8 months; HR, 0.46; 95% CI, 0.35-0.63; P=.001) and OS (9.3 vs 5.3 months; HR, 0.62; 95% CI, 0.46-0.83; P=.001) compared with single-agent pemetrexed. One-year survival rates were also higher with the combination (40.1% vs 21.9%). Similar results were seen when patients with squamous disease were excluded from the analysis. However, anemia and neutropenia were more frequent and 4 treatment-related deaths occurred in the combination arm.

Limitations of this study were that it included only 1 US center, making results somewhat less generalizable to the US population; the designation of PS 2 was based on assessment by 2 investigators at the treatment center, but that may not eliminate the element of subjectivity in such a designation; and almost 60% of patients were enrolled at a single center, raising the possibility that the bias in assigning PS at that institution may have potentially impacted the study results as a whole. The study did not provide any details on any other measures of functional status, details of comorbid burden, or quality-of-life data.

Table 2

Summary of Trials and Subset Analyses of Patients With Stage IV NSCLC and PS 2

View Table

Combination Therapy Comparisons: Patients with PS 2 on ECOG 1594⁵⁴ (comparison of 4 platinum doublets: cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, and carboplatin-paclitaxel) had a median survival of 4.1 months and a 1-year OS rate of 19%.⁵ The gemcitabine-cisplatin arm suggested a hint of better outcome with a median survival of 7.9 months in patients with PS 2, whereas paclitaxel-carboplatin was the least toxic. ECOG 1599 was a randomized phase II trial of gemcitabine-cisplatin or paclitaxel-carboplatin at attenuated doses.⁴⁶ The response rates, time to progression, median survival, and 1-year survival rates were not significantly different between the gemcitabine-cisplatin and paclitaxel-carboplatin arms (23%, 4.8 months, 6.9 months, and 25% vs 14%, 4.2 months, 6.2 months, and 19%, respectively). Although doublet therapy was considered feasible in patients with PS 2, outcomes remained inferior compared with those with PS 0 to 1. In a phase III trial conducted by the Norwegian Lung Cancer Group, 436 patients with PS 0 to 2 were randomized to carboplatin and either gemcitabine or pemetrexed.⁵⁰ No difference in OS was seen between the treatment arms (pemetrexed-carboplatin, 7.3 months; gemcitabine-carboplatin, 7.0 months; P=.63). Of the 96 evaluable patients with PS 2 (28%), median OS for the pemetrexed- and gemcitabine-based arms were 4.3 and 5.1 months, respectively. Interestingly, approximately 25% of patients enrolled on this study had a squamous histology, and no difference in outcomes was seen when patients with nonsquamous histology were analyzed separately.

In the phase III STELLAR 3 trial comparing paclitaxel-carboplatin versus paclitaxel poliglumex-carboplatin in patients with PS 2,⁸ median survivals and 1-year survival rates were similar in the 2 arms (7.9 months and 31% for paclitaxel poliglumex arm vs 8.0 months and 31% for the standard arm). CALGB 30402 was a randomized phase II trial that compared docetaxel-bortezomib and docetaxel-cetuximab in patients with PS 2.⁴⁸ Although the results from the cetuximab arm were numerically superior, they did not reach statistical significance (median PFS of 3.4 months and 6-month PFS rate of 27.8% vs 1.9 months and 13.8%, respectively).

Single-Agent Comparisons: The STELLAR 4 trial compared paclitaxel poliglumex and either single-agent gemcitabine or vinorelbine in treatment-naïve patients with PS 2.⁴⁷ The OS was similar between the arms. Median and 1-year survival rates were 7.3 months and 26%, respectively, for paclitaxel poliglumex versus 6.6 months and 26% for the control arm.

Table 3

Comparison of Outcomes of Patients With Stage IV NSCLC and PS 0 to 1 in Trials Including Patients With PS 0 to 2

View Table

Taken together, the median PFS and median OS with platinum-based combination chemotherapy are numerically and, in some studies, statistically superior to these measures in patients with PS 2 treated with monotherapy, but inferior to outcomes in patients with PS 0 to 1 (Table 3). Notably, this improvement in survival comes with higher toxicity, including the risk of treatment-related death with combination therapy, ranging from 3.0% to 7.4%.^5,50,51

In an attempt to identify prognostic markers among patients with poor PS, Lilenbaum et al⁵⁵ analyzed data from the STELLAR 3⁸ and STELLAR 4 trials.⁴⁷ In this analysis, factors that predicted for worse outcomes included serum albumin level of 3.5 g/dL or less, serum lactate dehydrogenase level greater than 200 IU/L, presence of extrathoracic metastases, and presence of 2 or more comorbid conditions.

Targeted Agents: Targeted agents are widely believed to provide effective and less-toxic therapy while allowing patients to maintain their functional independence.⁵⁶ As a result, great interest has been shown in using targeted agents in patients with poor PS.

Data from 2 trials suggest that erlotinib and gefitinib do not have a role in patients with poor PS without activating EGFR mutations. A randomized phase II study of erlotinib or standard chemotherapy (carboplatin-paclitaxel) with PFS as a primary end point found that in an unselected US population, median PFS for chemotherapy was superior to erlotinib (3.5 vs 1.9 months; HR, 1.45; 95% CI, 1.09-2.73; P=.018).¹¹ In another larger trial, gefitinib was not superior to placebo in terms of response rates or OS.⁵⁷ In contrast, patients with an activating EGFR mutation seem to benefit from EGFR tyrosine kinase inhibitors. A Japanese study of 30 patients with an EGFR mutations and poor PS reported a response rate of 66%. More significantly, most patients (≈80%) experienced an improvement in PS.⁵⁸

Crizotinib has been evaluated in patients with anaplastic lymphoma kinase (ALK)-positive NSCLC with PS 0 to 3 in clinical trials, with an excellent response.⁵⁹ Hence, it is worth trying crizotinib in patients with this fusion protein regardless of their PS.

In the FLEX study (cisplatin-vinorelbine ± cetuximab), approximately 18% of patients had PS 2.⁶⁰ Although not statistically significant, cetuximab was associated with a decreased risk of death in this cohort (HR, 0.74; 95% CI, 0.55-1.01). Currently, no evidence supports the use of bevacizumab in patients with poor PS. The results of the ToPPS trial (pemetrexed vs pemetrexed-bevacizumab vs pemetrexed-carboplatin-bevacizumab; ClinicalTrials.gov identifier: NCT00892710) should help answer this question.

An important finding is that studies restricted to the population with PS 2 report better outcomes than those reported for patients with PS 2 who are included in studies of patients with good PS.^8,47,51 This is likely secondary to a subjective bias of the treating oncologists, who may allow patients with a marginally better PS to enroll on a PS 2 study. Also, investigators likely report PS 2 more accurately in studies that include patients with PS 0 to 2. Despite this, and based on the accumulating data, it is becoming progressively clear that even patients with PS 2 experience better outcomes with combination therapy compared with monotherapy.

In summary, some patients with NSCLC and poor PS may be treated with combination chemotherapy. If this approach is chosen, the preferred treatment is carboplatin with either a taxane or pemetrexed (nonsquamous histology), based on trial data. Single-agent chemotherapy is reasonable to use at the discretion of the treating physician. Single-agent erlotinib should not be used in unselected patients instead of chemotherapy in the first-line setting in the absence of known EGFR mutations. Patients who are candidates for targeted therapy based on mutation status should be offered a trial of the targeted agent regardless of their PS. It is unclear how best to implement maintenance therapy strategies in these patients because mature trial data are not currently available, including those from subset analyses.

First-Line Therapy for Limited-Stage Disease

Patients with poor PS seem to have a worse response to chemotherapy. In a phase III trial comparing 3 different chemotherapy approaches, Roth et al⁶¹ found that only PS and gender predicted for response to therapy. Patients with good PS (ECOG PS 0, 1) had a median time to progression of 5.1 months compared with 3.2 months for those with poor PS (ECOG PS 2, 3) (P<.001).

The role of concurrent chemoradiation in patients with poor PS is unclear because data in this patient subset are lacking. In the phase III Intergroup trial, only approximately 5% of patients had ECOG PS 2; hence meaningful conclusions regarding this population cannot be drawn.⁶² One possible approach may be to try a couple of cycles of systemic chemotherapy, and if the patient tolerates therapy well and experiences an improvement in functional status, radiation could be added concurrently with further chemotherapy cycles.

First-line therapy for patients with extensive-stage SCLC depends on multiple factors (eg, whether patients have brain metastases). The authors' practice has been to try systemic chemotherapy in these individuals, because experience has shown that there is a subset of patients whose functional status improves after a decrease in tumor burden after therapy.

Relapsed Disease

Topotecan is the only FDA-approved therapy for relapsed small cell lung cancer. In a retrospective analysis of 479 patients, patients with PS 2 were able to tolerate topotecan at standard doses with similar tumor control and palliation of symptoms as those with PS 0 to 1.⁶³ Patients with PS 2 had a slightly greater incidence of grade 3/4 anemia, but other hematologic and nonhematologic toxicities were similar between the groups. However, OS was worse for patients with poor PS (36.3 weeks for PS 0 vs 16 weeks for PS 2). Despite this, topotecan may be reasonable to use in this setting for this patient cohort.