2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer

Abstract

ASCO produced the 2011 Focused Update based on phase III randomized clinical trials published on maintenance chemotherapy, addressing one question from the 2009 Guideline Update on chemotherapy for stage IV NSCLC: what is the optimal duration of first-line chemotherapy for stage IV NSCLC?

Introduction

The full American Society of Clinical Oncology (ASCO) Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer (NSCLC) was most recently published in November 2009 in Journal of Clinical Oncology (JCO).¹ The 2009 publication stated that new evidence may be published that would potentially warrant reconsideration of a recommendation in the guideline before the regularly scheduled update. Because of the rapid pace of research in lung cancer, there have been several phase III randomized clinical trials (RCTs) published on maintenance chemotherapy since the literature search cutoff date for that update. Concurrently, ASCO developed a new mechanism for providing evidence-based guidance: the focused update. Therefore, ASCO produced the 2011 Focused Update² based on these RCTs, addressing a single clinical question from the 2009 Guideline Update: What is the optimal duration of first-line chemotherapy for stage IV NSCLC?

Maintenance Chemotherapy in NSCLC

In addressing this clinical question, this 2011 Focused Update addresses only switch maintenance therapy. Switch maintenance therapy is alternative therapy administered to patients who have undergone first-line therapy for a specified number of cycles (usually four to six) and have either experienced a response or achieved stable disease. Continuation maintenance therapy is continuation of one or more drugs used during first-line therapy beyond four to six cycles. Second-line therapy is initiation of alternative therapy in patients whose disease has progressed during or after first-line chemotherapy.

Scope of Update and Literature Review

This focused update does not address the continuation of the same regimen of chemotherapy beyond the standard number of cycles recommended in the previous guideline, nor does it address the continuation of drugs contained in an initial regimen and continued beyond the chemotherapy included in the control arm. This update focuses on switch maintenance because the RCTs addressed this issue.

Changes From Prior Recommendation.

2009 Update Recommendation. In patients with stage IV NSCLC, first-line cytotoxic chemotherapy should be stopped at disease progression, or after four cycles in patients whose disease is not responding to treatment. Two-drug cytotoxic combinations should be administered for no more than six cycles. For patients who have stable disease or who respond to first-line therapy, evidence does not support the continuation of cytotoxic chemotherapy until disease progression, or the initiation of a different chemotherapy before disease progression.

2011 Focused Update Recommendation. In patients with stage IV NSCLC, first-line cytotoxic chemotherapy should be stopped at disease progression, or after four cycles in patients whose disease is stable but not responding to treatment. Two-drug cytotoxic combinations should be administered for no more than six cycles. For patients with stable disease or response after four cycles, immediate treatment with an alternative, single-agent chemotherapy such as pemetrexed in patients with nonsquamous histology, docetaxel in unselected patients, or erlotinib in unselected patients may be considered. Limitations of these data are such that a break from cytotoxic chemotherapy after a fixed course is also acceptable, with initiation of second-line chemotherapy at disease progression.

Changes from the previous recommendation are indicated in bold text.

The JCO publication of the focused update² summarizes an updated literature search. It reviews and analyzes new data from seven phase III RCTs regarding this recommendation (Recommendation A6) since the systematic review for the previous update. Trials using docetaxel, pemetrexed (for those with nonsquamous cell carcinoma), erlotinib, gefitinib, and gemcitabine have shown increased progression-free survival with maintenance therapy, with acceptable toxicity. In the study of pemetrexed and in one of two studies of erlotinib, overall survival was statistically significantly increased with switch maintenance therapy. The focused update notes that any improvement in progression-free survival is tempered by increases in adverse effects. Therefore, the change in the recommendation regarding switch maintenance generally applies to those patients whose fitness is sufficient to tolerate increased adverse effects. Furthermore, the recommendation for pemetrexed as an option for switch maintenance does not apply to those who received pemetrexed as part of their initial treatment.

According to ASCO guidelines regarding duration of first-line chemotherapy, patients with a radiologic response after four cycles of cytotoxic drug therapy may be considered for additional cycles of first-line chemotherapy (ie, cycles five and six). In keeping with this recommendation, the data on switch maintenance chemotherapy suggest that switching to a cytotoxic drug after four cycles of platinum-based chemotherapy seems to be more beneficial to patients with radiologic response. In contrast, when patients are switched to erlotinib for maintenance therapy, this trend toward greater benefit in responders is less apparent or nonexistent.

For clinicians, whether to offer continuation maintenance, switch maintenance, or a chemotherapy holiday to a patient who is still responding after four cycles of first-line chemotherapy is a decision with no absolute right or wrong answer; it must be shared with each patient individually. The decision must take into account subjective clinical factors such as magnitude of clinical benefit, virulence of disease, toxicity, tolerance, molecular markers, and patient preferences, none of which have been settled by the randomized studies published to date.

Recommendations

Table 1 provides a summary of the 2009 and 2011 recommendations. The JCO publication, data supplements, and an updated slide set, patient guide, and other resources are available at http://www.asco.org/guidelines/NSCLC.

Table 1.

Summary of Recommendations

Recommendation No.	Recommendation
First-line chemotherapy
A1	Evidence supports the use of chemotherapy in patients with stage IV NSCLC with ECOG/Zubrod performance status of 0, 1, and possibly 2.
A2	In patients with performance status of 0 or 1, evidence supports using a combination of two cytotoxic drugs for first-line therapy. Platinum combinations are preferred over nonplatinum combinations because they are superior in response rate, and marginally superior in overall survival. Nonplatinum therapy combinations are a reasonable in patients who have contraindications to platinum therapy. Recommendations A8 and A9 address whether to add bevacizumab or cetuximab to first-line cytotoxic therapy.
A3	Available data support the use of single-agent chemotherapy in patients with performance status of 2. Data are insufficient to make a recommendation for or against using a combination of two cytotoxic drugs in patients with performance status of 2.
A4	The evidence does not support the selection of a specific first-line chemotherapy drug or combination based on age alone.
A5	The choice of either cisplatin or carboplatin is acceptable. Drugs that may be combined with platinum include the third-generation cytotoxic drugs docetaxel, gemcitabine, irinotecan, paclitaxel, pemetrexed, and vinorelbine. The evidence suggests that cisplatin combinations have a higher response rate than carboplatin and may improve survival when combined with third-generation agents. Carboplatin is less likely to cause nausea, nephrotoxicity, and neurotoxicity than cisplatin but more likely to cause thrombocytopenia.
A6	In patients with stage IV NSCLC, first-line cytotoxic chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is stable but not responding to treatment. Two-drug cytotoxic combinations should be administered for no more than six cycles. For patients with stable disease or response after four cycles, immediate treatment with an alternative, single-agent chemotherapy such as pemetrexed in patients with nonsquamous histology, docetaxel in unselected patients, or erlotinib in unselected patients may be considered. Limitations of these data are such that a break from cytotoxic chemotherapy after a fixed course is also acceptable, with initiation of second-line chemotherapy at disease progression.
A7	In unselected patients, erlotinib or gefitinib should not be used in combination with cytotoxic chemotherapy as first-line therapy. In unselected patients, evidence is insufficient to recommend single-agent erlotinib or gefitinib as first-line therapy. First-line use of gefitinib may be recommended for patients with activating EGFR mutations. If EGFR mutation status is negative or unknown, then cytotoxic chemotherapy is preferred (see Recommendation A2).
A8	Based on the results of one large phase III randomized controlled trial, the Update Committee recommends the addition of bevacizumab, 15 mg/kg every 3 weeks, to carboplatin/paclitaxel, except for patients with squamous cell carcinoma histologic type, brain metastases, clinically significant hemoptysis, inadequate organ function, ECOG performance status > 1, therapeutic anticoagulation, clinically significant cardiovascular disease, or medically uncontrolled hypertension. Bevacizumab may be continued, as tolerated, until disease progression.
A9	On the basis of the results of one large phase III randomized controlled trial, clinicians may consider the addition of cetuximab to cisplatin/vinorelbine in first-line therapy in patients with EGFR-positive tumor as measured by immunohistochemistry. Cetuximab may be continued, as tolerated, until disease progression.
Second-line chemotherapy
B1	Docetaxel, erlotinib, gefitinib, or pemetrexed is acceptable as second-line therapy for patients with advanced NSCLC with adequate performance status when disease has progressed during or after first-line, platinum-based therapy.
B2	The evidence does not support the selection of a specific second-line chemotherapy drug or combination based on age alone.
Third-line chemotherapy
C1	When disease progresses during or after second-line chemotherapy, treatment with erlotinib may be recommended as third-line therapy for patients with performance status of 0 to 3 who have not received prior erlotinib or gefitinib.
C2	The data are not sufficient to make a recommendation for or against using a cytotoxic drug as third-line therapy. These patients should consider experimental treatment, clinical trials, and best supportive care.
Molecular analysis
D1	Evidence is insufficient to recommend routine use of molecular markers* to select systemic treatment in patients with metastatic NSCLC.
D2	In order to obtain tissue for more accurate histologic classification or for investigational purposes, Update Committee supports reasonable efforts to obtain more tissue than what is contained in a routine cytology specimen.

NOTE. Bold font indicates changes in 2011 Focused Update.¹

Abbreviations: ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; NSCLC, non–small-cell lung cancer; TKI, tyrosine kinase inhibitor.

^*In April 2011, the American Society of Clinical Oncology issued Provisional Clinical Opinion regarding EGFR testing. It will be incorporated into future updates of NSCLC guideline: On the basis of the results of five phase III randomized controlled trials, patients with NSCLC who are being considered for first-line therapy with EGFR TKI (patients who have not previously received chemotherapy or EGFR TKI) should have their tumor tested for EGFR mutations to determine whether EGFR TKI or chemotherapy is the appropriate first-line therapy (http://www.asco.org/pco/egfr).

Authors

The 2011 Focused Update of the 2009 ASCO Clinical Practice Guideline Update on chemotherapy for stage IV non–small-cell lung cancer was developed and written by Christopher G. Azzoli, Sarah Temin, Timothy Aliff, Sherman Baker Jr, Julie Brahmer, David H. Johnson, Janessa L. Laskin, Gregory Masters, Daniel Milton, Luke Nordquist, William Pao, David G. Pfister, Steven Piantadosi, Joan H. Schiller, Reily Smith, Thomas J. Smith, John R. Strawn, David Trent, and Giuseppe Giaccone.

THE BOTTOM LINE: ASCO Guideline Focused Update.

2011 FOCUSED UPDATE OF 2009 AMERICAN SOCIETY OF CLINICAL ONCOLOGY CLINICAL PRACTICE GUIDELINE UPDATE ON CHEMOTHERAPY FOR STAGE IV NON–SMALL-CELL LUNG CANCER

Intervention

• Switch maintenance (alternative therapy administered to patients who have undergone first-line therapy for a specified number of cycles [usually four to six] and have either experienced a response or achieved stable disease)

Target Audience

• Medical oncologists

Recommendation

• In patients with stage IV NSCLC, first-line cytotoxic chemotherapy should be stopped at disease progression or after four cycles in patients whose disease is stable but not responding to treatment. Two-drug cytotoxic combinations should be administered for no more than six cycles. For patients with stable disease or response after four cycles, immediate treatment with an alternative, single-agent chemotherapy such as pemetrexed in patients with nonsquamous histology, docetaxel in unselected patients, or erlotinib in unselected patients may be considered. Limitations of these data are such that a break from cytotoxic chemotherapy after a fixed course is also acceptable, with initiation of second-line chemotherapy at disease progression.

• Note: this represents an update of a single recommendation from the 2009 ASCO Guideline Update

Methods

• Systematic review and analysis of medical literature by an Expert Panel Update Committee

Additional Information

The 2009 Guideline Update, a data supplement of evidence tables, and clinical tools can be found at http://www.asco.org/guidelines/NSCLC.

Only Recommendation A6 is changed by this update. To view the original clinical questions corresponding to all recommendations, please refer to Data Supplement 3.

Appendix

Supplemental Methods

Patient selection.

The following variables were recorded: a depersonalized medical record number, date of birth, date of the first clinic visit, patient's demographics information (sex, ethnicity, smoking status, and pack-years), patient's Eastern Cooperative Oncology Group (ECOG) performance status (PS) at the first visit, tumor histology, tumor genetic background, disease stage at diagnosis (because cases were collected before 2010, the 6th edition TNM was used³), the depersonalized oncologist/physician of record, clinical trial enrollment, and treatment received (including surgery, radiotherapy, and systemic therapy). All data were entered in a secure, Web-based database created by the investigators.

Determination of evidence-based versus non–evidence-based therapies.

Because the study retrospectively collected data from periods between July 1, 2007 and January 1, 2010, the evidence-based recommendations detailed in Table 1 were meant to be broad and reflect accepted data-driven therapies that were available during those years. When using NCCN guidelines from 2007 to 2010.⁴ to add to Table 1, we included only NCCN categories 1 (recommendation is based on high level evidence—eg, randomized controlled trials—and there is uniform NCCN consensus), 2A (recommendation is based on lower level evidence and there is uniform NCCN consensus), and 2B (recommendation is based on lower level evidence and there is nonuniform NCCN consensus, but no major disagreement). ASCO guidelines from 2003 and 2009, as well as more recent randomized trials, were also used to extrapolate evidence-based treatment recommendations.^5(pp11-13) Table 1 indicates when the recommendation was based on a randomized phase III trial. The medical oncologists or other providers at BIDMC did not follow a prespecified set of service guidelines for care of patients with NSCLC. Patients who participated in therapeutic clinical trials followed the trial-specific protocols.

Supplemental Results

Identification of patients.

Of the 622 patients with a diagnosis of lung cancer, as inferred by an International Classification of Diseases 9th revision (ICD-9) of 162.X (malignant neoplasm of trachea bronchus and lung), at BIDMC from July 1, 2007 to July 31, 2009, most were excluded as a result of (1) having a diagnosis of cancer but not of NSCLC, (2) being seen as a “second-opinion visit” and not followed at BIDMC, (3) being seen by a non–medical oncology provider, (4) not receiving care at our center after the initial visit (refer to the Methods section).

Adherence to evidence-based treatment strategies in stage IV NSCLC.

The three most common first-line chemotherapy regimens used for the entire 185-patient cohort (101 patients with stage IV NSCLC, of whom 76 had their evidence-based care status determined) were carboplatin-paclitaxel (25 patients), carboplatin-gemcitabine (15 patients), and carboplatin-paclitaxel with bevacizumab (nine patients). The most common single-agent first-line regimen used was vinorelbine (seven patients), followed by erlotinib (five patients). For second-line treatments, the most common regimens used were pemetrexed (23 patients), erlotinib (11 patients), and docetaxel (five patients). All third-line regimens were single agents, with treatment distributed between pemetrexed (four patients), docetaxel (four patients, with two as part of a clinical trial), gemcitabine (three patients), erlotinib (three patients), vinorelbine (two patients), carboplatin (one patient), and crizotinib (one patient, as part of a clinical trial).

Supplemental Discussion

BR. 21 trial.

In that trial of 731 patients, 49% had received two prior chemotherapy regimens (i.e., would qualify as being part of the third-line setting of care for NSCLC). Those patients were randomized to either erlotinib 150 mg daily or placebo, and the RR was 8.9% and < 1% in the erlotinib and placebo groups (P < .001), with a PFS of 2.2 months and 1.8 months for erlotinib and placebo (HR = 0.61.; P < .001), and median OS of 6.7 months and 4.7 months for erlotinib and placebo, respectively (HR = 0.70; P < .001).¹⁷

Strengths and weakness of the study.

The present study had some limitations. One was that the sample size of 185 patients included in the study, with only 150 patients with enough data to determine evidence-based care status, coupled with the high adherence to evidence-based care in stages I-III, may have compromised statistical power to detect a significant correlation between patient, tumor, and provider characteristics and the type of care received. It is also possible that if we had restricted our level of evidence-based collection to the equivalent of NCCN categories 1 and 2A (ie, randomized clinical trials and uniform expert consensus, respectively), the rate of adherence to that level of evidence would have been lower for stages I to III NSCLC. Additional limitations of the study were that, because of its design, it did not intend to and was not able to compare the associated costs of care or outcomes of patients receiving to those not receiving evidence-based care, and it relied on a medical chart review to capture best supportive care. Another limitation was the limited number of patients that composed the third-line setting of stage IV NSCLC. Despite these limitations, the study also had significant strengths. These included capture of patients with a well-defined diagnosis of NSCLC, a prospective unbiased practice of medical thoracic oncologists in an academic medical center, smoking history, tumor genetic characteristics, and modes of therapy provided (surgery, radiation, and systemic therapy). These characteristics are seldom available when analyzing large insurance- or government-based claim databases and using ICD-9 codes to infer a diagnosis of NSCLC.

Table A1.

Odds Ratios of Various Factors and Adherence Rate to Evidence-Based Treatment From a Multivariate Logistic Regression Analysis

Factor	Odds Ratio	95% CI
Stage: low (I-III) v stage IV	16.33	1.94 to 137.73
ECOG PS: 0/1 v ECOG PS 3	4.77	0.42 to 54.70
ECOG PS: 2 v ECOG PS 3	2.91	0.16 to 51.94
Smoking: current v never	5.33	0.59 to 48.10
Ethnicity: nonwhite v white	2.48	0.43 to 14.22
Smoking: former v never	3.85	0.75 to 19.64
Sex: female v male	1.60	0.44 to 5.83
Age	1.06	0.99 to 1.13
Physician C v physician A	0.63	0.11 to 3.64
Physician B v physician A	0.44	0.09 to 2.18

Abbreviation: ECOG PS: Eastern Cooperative Oncology Group performance status.

Table A2.

Rate of Adherence to Guidelines by Line of Therapy in Patients With Stage IV NSCLC With Determined Evidence-Based Care Status

Line	Evidence-Based Care		Non–Evidence-Based Care		Total
	No.	%	No.	%
First	72	95	4	5	76
Second	40	95.2	2	4.8	42
Third	6	33.3	12	66.7	18

Abbreviation: NSCLC, non–small-cell lung cancer.

Authors' Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Christopher G. Azzoli, Genentech, sanofi-aventis, Eli Lilly Expert Testimony: None Other Remuneration: None

Author Contributions

Conception and design: Christopher G. Azzoli, Giuseppe Giaccone

Administrative support: Sarah Temin

Collection and assembly of data: All authors

Data analysis and interpretation: Christopher G. Azzoli, Giuseppe Giaccone

Manuscript writing: All authors

Final approval of manuscript: All authors