Among the issues that faced the National Comprehensive Cancer Network (NCCN) Lung Cancer Panel, perhaps the role of adjuvant therapy for patients with early-stage IA non-small cell lung cancer (NSCLC) created the most controversy, reported David S. Ettinger, MD, of The Sydney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore. Other revisions to the 2008 NCCN guidelines for NSCLC focused on screening with computed tomography (CT), positron emission tomography (PET) in the workup of lung cancer, treatment of locally advanced disease, and systemic therapy for stage IV and recurrent NSCLC.
The NCCN Lung Cancer Panel issued a prevention and screening statement in regard to CT. At present, the panel does not recommend the routine use of screening spiral CT as standard clinical practice (category 3); however, there is major disagreement, which is reflected in the category 3 designation. The panel did recommend that high-risk individuals participate in a clinical trial evaluating CT screening. Although the panel considered the Henschke and Bach studies (N Engl J Med 2006;355:1763−1771; JAMA 2007;297:953−961) regarding the use of CT in lung cancer screening, Dr. Ettinger, who is Chair of the Lung Cancer Panel, added, “we all await the national study that is to be out in 2009 regarding the routine use of spiral CT. The jury is out on whether CT screening decreases mortality from lung cancer.”
Included in the initial evaluation for the diagnosis of NSCLC are pathology review, CT of the chest and upper abdomen, blood work, and smoking cessation counseling. “Stop cigarette smoking, stop lung cancer,” Dr. Ettinger emphatically reminded. The initial workup does not include a PET scan. However, when conducting a pretreatment clinical assessment for almost all stages of disease, Dr. Ettinger emphasized, mediastinoscopy and PET scan are included in the 2008 guidelines. In this setting, “the mediastinoscopy remains the gold standard for staging the mediastinum, and PET is valuable in the assessment of distant metastasis,” he added. However, PET cannot render a histologic diagnosis. Furthermore, the recommendation for mediastinoscopy was changed to pathologic mediastinal lymph node evaluation for stage IIIA (T1–3, N2) disease only.
Although there are several dilemmas in the management of patients with local and locally advanced disease, the good news is that “tens of thousands of patients are cured of lung cancer every year,” declared Mark G. Kris, MD, of Memorial Sloan-Kettering Cancer Center, who serves on the NCCN Lung Cancer Panel.
The standard of care is still anatomic resection for stage IA (T1, N0) disease; however, adjuvant treatment after surgery is controversial. With negative margins, adjuvant treatment is not currently recommended. Although some members of the panel thought that chemotherapy could be recommended for high-risk patients, there was no agreement, and it was revised to a category 3 designation. With positive margins, repeat resection is recommended. Chemoradiation or radiation therapy can also be used for positive margins, but there is less evidence for these options (category 2B). The addition of chemotherapy to either repeat resection or chemoradiation was also changed to category 3.
However, adjuvant chemotherapy plays a definitive role after complete resection in patients who have stage IIA or IIB (T1–2, N1) disease. Cisplatin-based chemotherapy is the standard of care in these patients, with category 1 evidence, Dr. Kris pronounced. “We emphatically recommend adjuvant cisplatin-based chemotherapy for completely resected stages II and IIIA disease and mediastinal radiation for IIIA [T1–2, N2],” Dr. Kris reported. The 2008 guidelines describe five different cisplatin-based regimens in this setting; the major regimens are cisplatin/vinorelbine (which has been studied the most), cisplatin/etoposide, and cisplatin/vinblastine. There are other regimens for patients who cannot take cisplatin because of comorbidities or intolerance.
Adjuvant radiotherapy was another issued tackled by the panel. Like the 2007 recommendations by the American Society of Clinical Oncology (ASCO), NCCN does not recommend adjuvant radiation for patients with completely resected stage I or II disease. For stage IIIA disease, the general consensus was that radiation may be of benefit, Dr. Kris said. In the 2008 guidelines for stage IIIA disease with negative margins, the panel now recommends that mediastinal radiation be added to chemotherapy.
Several approaches have been taken to treat patients with locally advanced stage IIIA disease, including induction chemotherapy followed by resection, surgery followed by adjuvant chemotherapy, or definitive concurrent chemoradiation (ie, no surgery). One dilemma in treating locally advanced disease is whether chemotherapy should be given before or after surgery. Dr. Kris conducted a mini-literature analysis of the response and resectability of preoperative chemotherapy in eight trials containing more than 400 patients with stage IIB/IIIA NSCLC. The findings supported the rationale for offering induction chemotherapy: an impressive median overall response rate of 71%, a median resection rate of 58%, and a median overall survival rate of almost 2 years.
“I am a proponent of induction chemotherapy, and I recommend it for these reasons,” Dr. Kris explained. If micrometastases endanger the lives of our patients with locally advanced NSCLC, chemotherapy is the way we attack it, he added. “It makes sense to fight it as soon as possible, and I would give induction therapy as soon as the diagnosis and staging were clear.”
However, there are advantages to performing surgery and then giving adjuvant chemotherapy, Dr. Kris acknowledged. Surgery permits gold-standard staging and the ability to obtain tissue. With the trend in management of NSCLC moving toward personalized therapy, Dr. Kris continued, this approach would enable sufficient tissue after surgery to be used to tailor therapy in the adjuvant setting.
Another dilemma in treating locally advanced disease is the question of surgery versus radiation therapy. According to the North American intergroup trial 0139 (Albain KS et al. J Clin Oncol 2005;23[16S]:7014), there appeared to be no difference in the outcomes of patients with stage IIIA disease who received definitive chemoradiation compared with an induction regimen followed by surgery. However, the investigators did find that for those patients who would need a pneumonectomy, it appeared that the group treated with concurrent chemoradiation did better than did those who had induction therapy and surgery. Furthermore, “for the group that needed a lobectomy, just the opposite was seen; those patients seemed to do better with a surgical approach,” Dr. Kris stated.
Factors favoring radiation therapy, according to Dr. Kris, include fewer early deaths and potentially better outcomes for patients who require pneumonectomy. Treatment availability may represent another advantage of radiation therapy. “There are a greater number of high-quality, state-of-the-art radiation facilities across America than there are high-volume surgery centers,” Dr. Kris said. Basically, the NCCN recommends both modalities, with category 1 evidence supporting concurrent chemoradiation. The 2008 guidelines designated cisplatin/etoposide and cisplatin/vinblastine as the preferred regimens for chemoradiation in this setting, assigning a category 2B ranking to the paclitaxel/carboplatin combination.
Survivorship in NSCLC is an issue that must be addressed; however, there is no information in the medical literature about these patients, according to Dr. Kris. Each year, thousands of patients receive treatment but then are without a plan of care. Because of exposure to tobacco, patients are at very high risk for a second primary lung cancer and should receive aggressive smoking-cessation counseling. They are also at risk for other smoking-related diseases (such as chronic obstructive pulmonary disease) and late-onset adverse effects because irradiation to the chest accelerates cardiovascular disease; survivors often die of heart disease if it is not monitored. Therefore, stress tests should be done, and lipid levels should be assessed. Radiation therapy also accelerates osteoporosis. Thus, surviving patients need careful surveillance using the NCCN guidelines.
Forty percent of lung cancer is advanced, metastatic, recurrent stage IV disease, Dr. Ettinger asserted. Considerations in the treatment of isolated metastasis should include patient factors (such as performance status [PS] and comorbidity), the possibility of resection for the primary tumor or metastatic site, and the prognostic significance of the timing of presentation (synchronous vs metachronous).
Single sites of metastasis include the brain, adrenal glands, and the contralateral or ipsilateral lung. The 2008 NCCN guidelines for solitary brain metastases recommend resection of the brain lesion plus whole-brain or stereotactic radiosurgery. For an isolated adrenal metastasis, there are fewer available data; therefore, resection of the adrenal lesion carries a category 3 designation. As for solitary nodes in the contralateral or ipsilateral lung, they should be treated as primary lung tumors if both are curable.
In terms of systemic therapy and best supportive care for recurrence and metastasis, the 2008 version of the guidelines removed patients with a PS of 2 from the grouping with patients with a PS of 0 and 1. For patients with a PS of 0 or 1, if the criteria are met for bevacizumab (Avastin), they should receive bevacizumab as first line with chemotherapy. “If they are not met, it’s chemotherapy,” Dr. Ettinger explained. For those with a PS of 2, the recommended treatment is chemotherapy, and for those with a PS of 3 or 4, it is best supportive care.
For second-line therapy of progressive disease, patients with a good PS (0−2) should be given the option of docetaxel (Taxotere), pemetrexed (Alimta), or erlotinib (Tarceva). Again, for those with a poor PS (3 or 4), best supportive care is recommended. “Clinical trial trumps everything,” Dr. Ettinger reminded the audience, “so if the patient is eligible for a clinical trial…that’s justified to put the patient on the trial.”
Two phase III trials—Eastern Cooperative Oncology Group (ECOG) E4599 and AVAiL—have studied the use of bevacizumab in combination therapy for NSCLC. In E4599 (Sandler AB et al. J Clin Oncol 2005;23[16S]:4; N Engl J Med 2006;355:2542–2550), the regimens compared were paclitaxel/carboplatin and paclitaxel/carboplatin/bevacizumab. The response rate was higher with the addition of bevacizumab (27% vs 10%), as was overall survival. “We never talk about 2-year survival in a phase III trial of 22%,” Dr. Ettinger admitted. Although bevacizumab has been associated with an increase in serious bleeding, he said, this triple-drug regimen is now the ECOG reference regimen for the first-line treatment of advanced non-squamous cell NSCLC.
The AVAiL trial (Manegold C et al. J Clin Oncol 2007;25[18S]:LBA7514), which compared the doublet of gemcitabine (Gemzar)/cisplatin with and without bevacizumab, demonstrated similar promising results. “The overall survival is not out [data are not available yet], but progression-free survival is statistically better [with bevacizumab],” Dr. Ettinger added.