ASCO GUIDELINESS FOR STAGE IV LUNG CANCER

November 24, 2009 — Guidelines for using chemotherapy in the treatment of stage 4 nonsmall-cell lung cancer (NSCLC) have been updated by the American Society of Clinical Oncology (ASCO), and now include details of when to use targeted therapies.

The update, the first since 2003, was published online November 16 in the Journal of Clinical Oncology and on the ASCO Web site . It was prompted by a large number of new peer-reviewed studies, say the authors, led by Christopher Azzoli, MD, from the Memorial Sloan-Kettering Cancer Center in New York City.

The new recommendations are based primarily on statistically significant improvements in overall survival documented in prospective randomized controlled trials, say the authors. They add that treatment strategies that demonstrated an improvement only in progression-free survival prompted greater scrutiny about issues such as toxicity and quality of life.

First-Line Therapy

The recommendations for using cytotoxics in first-line treatment have not changed, but there are several additional recommendations about the use of targeted agents.

The guidelines stipulate that:

• For patients with a performance status of 0 or 1, a platinum-based 2-drug combination of cytotoxic drugs is recommended.
• For patients with a performance status of 2, single-agent chemotherapy is recommended.
• Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy.
• First-line chemotherapy should be stopped at disease progression, or after 4 cycles in patients not responding to treatment. Two-drug cytotoxic combinations should be administered for no more than 6 cycles.

Platinum compounds are preferred over nonplatinum compounds because they are superior in response rate and marginally superior in overall survival, the authors explain. The choice of either cisplatin (Platinol) or carboplatin (Paraplatin) is acceptable because neither is consistently superior, they note; cisplatin might have better efficacy but carboplatin might have less toxicity.

There are not enough data to narrow down the selection of the platinum-based doublet on the basis of efficacy alone, and the clinician must often choose which drugs to use on the basis of other factors, including dosage schedules and adverse events, they add. The choice of a second drug in the platinum-based doublet can include the following: docetaxel (Taxotere), gemcitabine (Gemzar), irinotecan (Camptosar), paclitaxel (Taxol), pemetrexed (Alimta), or vinorelbine (Navelbine).

New in the update are recommendations on the use of targeted agents in first-line treatment, as follows:

• The addition of bevacizumab (Avastin) to carboplatin/paclitaxel is recommended, except in patients with certain characteristics (i.e., those with squamous cell carcinoma histology, brain metastases, clinically significant hemoptysis, inadequate organ function, a performance status greater than 1, therapeutic anticoagulation, clinically significant cardiovascular disease, or medically uncontrolled hypertension).
• The addition of cetuximab (Erbitux) to cisplatin/vinorelbine can be considered in patients with tumors testing positive for epidermal growth-factor receptor (EGFR), as measured by immunohistochemistry.
• First-line gefitinib (Iressa) use can be recommended for patients with activating EGFR mutations. However, if EGFR mutation status is negative or unknown, cytotoxic chemotherapy is preferred.
• Erlotinib (Tarceva) or gefitinib should not be used in first-line therapy in combination with cytotoxics in unselected stage 4 NSCLC patients.

Second- and Third-Line Treatment

There has been a change in the drugs recommended for use in second-line therapy. Previously, only docetaxel (Taxotere) was recommended for use after progression on platinum-based first-line therapy, and gefitinib was recommended after a failure of both platinum-based therapies and docetaxel. Now the guidelines state that docetaxel, gefitinib, erlotinib, and pemetrexed are acceptable as second-line therapies.

The guideline committee notes that pemetrexed was recently approved by the US Food and Drug Administration for maintenance therapy in NSCLC, but this is based on recently presented data that were "outside the scope" of the comprehensive data review undertaken.

Third-line therapy with erlotinib can be recommended for patients with a performance status of 0 to 3 who have progressed on or after second-line therapy and who have not previously received erlotinib or gefitinib. There is not enough evidence to make a recommendation for or against using a cytotoxic drug as a third-line therapy, the authors explain.

There is insufficient evidence to recommend the routine use of molecular markers to select systemic treatment in patients with metastatic NSCLC. "However, emerging data suggest that this paradigm is changing," write the authors. Some agents seem to be more effective or less toxic with certain histological subtypes, and recent studies have shown that therapy could be improved by selecting drugs based on molecular markers.

In addition, the updated guidelines considered the treatment of elderly patients, but conclude that age should not determine what treatment a patient receives. The committee also acknowledges that disparities exist, highlighting a recent study that found that only 36% of African American patients with stage 4 NSCLC receive first-line chemotherapy.

"Ethnic and racial minorities experience worse outcomes [than] whites in all stages of lung cancer, and these disparities are frequently due to communication barriers between doctors and their patients," Dr. Azzoli said in a statement. "When patients receive uniform clinical care, these disparities are minimized," he added.

"The survival of patients with stage 4 NSCLC remains poor, and all eligible patients should be encouraged to participate in clinical research trials at any time during the course of their disease," the authors conclude.

Large Differences in Costs

A cost-effectiveness analysis is "beyond the scope of this guideline and did not impact on the recommendations," the authors explain, but note that the costs of the drugs vary, and provide some cost estimates in a table, reproduced in part below. The cost estimates are based on data from the Centers for Medicare and Medicaid Services.

Estimated Cost for 2 Cycles of Therapy

Drug	Estimated Cost ($)
Bevacizumab	14,040
Carboplatin	146
Cetuximab	18,981
Cisplatin	68
Docetaxel	5,060
Erlotinib	9,114
Gefitinib	4,255
Gemcitabine	6,914
Irinotecan	527
Paclitaxel	201
Pemetrexed	9,682
Vinorelbine	257

Dr. Azzoli reports having received research funding from Allos Therapeutics, Sanofi-Aventis, and Genentech BioOncology. The financial relationships of several of his coauthors are detailed in the paper.

J Clin Oncol. Published online November 16, 2009. Abstract