Nonsmall Cell Lung Cancer

The first step in treatment of NSCLC involves confirmation of the clinical stage and determination of resectability of the tumor. This decision should always be made by a thoracic surgeon who routinely performs lung cancer surgery. Treatment options depend on the advancement of disease (i.e., local, locally advanced, or metastatic), PS, and eligibility for resection.

Local Disease (Stages 1A, 1B, and II A)

Local disease encompasses stages IA through IIA and is associated with a favorable prognosis because approximately 40% to 60% of patients are expected to live more than 5 years from diagnosis. Goals of therapy are curative in local disease, and surgery is the mainstay of treatment. Stage IA tumors are rarely seen clinically and may be treated with surgery alone. In this case, neoadjuvant or adjuvant therapy has not been adequately studied to know if it conveys a benefit. If surgical margins are positive, radiotherapy or re-resection is recommended.19 Stages IB, IIA, and locally advanced IIB NSCLC is treated with adjuvant chemotherapy. Patients who have positive or questionable margins may receive radiation therapy, which typically is administered with the adjuvant chemotherapy. The regimen of choice in this setting is not clea^ however, clinical trials demonstrating the most benefit used cisplatin-vinorelbine.19,4

Locally Advanced Disease (Stages IIB and I IIA)

Patients with locally advanced disease should also be considered for surgery. Neoad-juvant chemotherapy with concurrent radiotherapy can be used prior to surgery, although this practice varies from institution to institution. Progression of disease during induction therapy may preclude surgery, and the regimen should be altered. If there is a response, surgical resection can be attempted, with or without additional adjuvant chemotherapy. Nonresectable locally advanced disease may be treated with both an active platinum-containing regimen and radiotherapy.

Advanced or Metastatic Disease (Stages IIIB and IV)

Advanced disease is treated with chemotherapy if the patient has an acceptable ECOG PS score (0-1). Platinum-containing doublets have produced the highest overall response rates (25-35%) and survival times (30-40% 1-year survival) in well-performing patients with advanced disease. A number of different platinum doublet treatment regimens have been used in this setting. In some patients with stage IIIB disease, cisplatin and etoposide may be given concurrently with radiotherapy. However, treating unresectable stage III patients with a platinum-containing doublet regimen and omitting the radiation is common. The optimal regimen has yet to be determined. There has been some debate about the equivalence of cisplatin and carboplatin. To address this question, a recent meta-analysis was performed, which indicated that cisplatin was superior to carboplatin when combined with another agent (see below) in advanced-stage NSCLC.43 As with any meta-analysis, the methodology is subject to limitations leaving clinicians to make their own decision. Additionally, two nonplatinum-containing regimens have been shown to have similar response and survival benefits. Both gemcitabine-paclitaxel and gemcitabine-docetaxel produce response durations and survival times similar to the platinum-containing doublet regimens. These regimens may be substituted when patients are unlikely to tolerate the toxicity of platinum regimens owing to comorbidities or other factors. NSCLC chemotherapy doublets that are considered generally equivalent include:

• Paclitaxel-cisplatin

• Paclitaxel-carboplatin

• Cisplatin-gemcitabine

• Cisplatin-docetaxel

• Carboplatin-docetaxel

• Cisplatin-vinorelbine

• Gemcitabine-paclitaxel

• Gemcitabine-docetaxel

• Cisplatin-pemetrexed

A large randomized trial comparing the first four regimens reported similar response rates and survival with all treatments, although there was less life-threatening toxicity and treatment-related death associated with paclitaxel-carboplatin. Consequently, one may argue that paclitaxel-carboplatin is the treatment of choice. However, the carboplatin-paclitaxel regimen used in the trial infused paclitaxel over 24 hours, which is uncommon in clinical practice. The most common carboplatin-paclitaxel regimen infuses a higher dose of paclitaxel over 3 hours in the clinic rather than admit patients to the hospital for a 24-hour infusion. It is unfair to extrapolate the toxicity advantage from this trial to the commonly used 3-hour paclitaxel infusion, and consequently, there is not a single best regimen.

Taxanes (docetaxel and paclitaxel) are frequently employed in advanced NSCLC. Albumin-bound paclitaxel may be substituted for docetaxel or paclitaxel in patients who have experienced hypersensitivity reactions to taxanes despite antihypersensit-ivity premedication. The albumin-bound paclitaxel formulation does not include excipients such as Cremophor-EL that are thought to be the primary cause of frequent taxane-related reactions.

Targeted Agents While it is unclear exactly which combination is the best, new research is being aimed at adding targeted agents to platinum regimens. Adding beva-cizumab to the carboplatin-paclitaxel (3-hour infusion) regimen increases response rates and prolongs progression-free survival by 1.7 months and overall survival by 2.3 months.34 Consequently, carboplatin-paclitaxel and bevacizumab are arguably the new standard of care. Based on the inclusion/exclusion criteria for this study, bevacizumab is recommended when the patient meets the following criteria:

• Nonsquamous cell histology (NSCLC only)

• History negative for hemoptysis

• History negative for untreated CNS metastasis

• No concurrent anticoagulation therapy (i.e., enoxaparin, heparin, or warfarin). In clinical trials, low-dose aspirin was permissible.

• Chemotherapy regimen that does not have significant (greater than 10%) risk of thrombocytopenia.

Interestingly, bevacizumab does not show synergy with all regimens; when combined with cisplatin and gemcitabine, no survival advantage is seen. Consequently, it should only be used with carboplatin and paclitaxel.

The anti-EGFR monoclonal antibody cetuximab has been shown to improve survival when combined with cisplatin and vinorelbine. The FLEX trial demonstrated a 1.2-month survival advantage of cetuximab when added to cisplatin and vinorelbine in recurrent or metastatic NSCLC (Stages IIIB-IV). The study population consisted of chemotherapy-naive patients with PS 0 to 2 that demonstrated positive tumor staining for EGFR by immunohistochemistry. It is unclear how this regimen compares to bevacizumab plus carboplatin and paclitaxel. Because bevacizumab was proven effective first and the survival advantage appears superior; cisplatin, vinorelbine, and cetuximab will likely only be used in patients with a contraindication to bevacizumab (squamous cell histology). Adding EGFR TKIs (erlotinib or gefitinib) to chemotherapy provides no benefit.

Poorly Performing Patients Treating patients with a PS of 2 is a subject of debate. While PS 2 patients typically have inferior survival rates and higher toxicity to platinum chemotherapy than higher-performing patients, low-toxicity single-agent regimens may offer a survival advantage in this subset. Use of these regimens also presents a method of providing symptomatic care for advanced-stage patients. Agents such as pemetrexed, gemcitabine, and docetaxel may be used in this scenario. In PS 3 or 4 patients, chemotherapy typically results in high rates of toxicity and fails to convey a survival benefit. Consequently, treatment should be aimed at relief of symptoms instead of a definitive cure.

Recurrent and Progressive Disease

Although patients may experience a response to initial therapy, disease recurs in many cases. If the recurrence is localized, surgery options may be assessed. If the patient's PS remains acceptable (0-1), second-line systemic chemotherapy has been shown to improve survival. Although platinum doublets may be used at this point in care, a single-agent therapy with docetaxel, pemetrexed, or erlotinib is recommended.44 Recurrences in poorly performing patients (3-4) usually are not treated with chemotherapy and are instead treated with supportive care. Additional recurrences (e.g., third-line therapy) may be treated with erlotinib if not used previously. Otherwise, repeat single-agent therapy or administer best supportive care.

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