Anish Thomas, Christina Brzezniak, and Giuseppe Giaccone
EPIDEMIOLOGY
■Lung cancer, broadly divided into small cell lung cancer (SCLC) and non–small cell lung cancer (NSCLC), is the leading cause of cancer death in both men and women in the United States and worldwide.
■An estimated 226,160 new cases of lung and bronchus cancer (116,470 in men and 109,690 in women) were diagnosed in 2012 in the United States, resulting in 160,340 deaths (87,750 in men, 72,590 in women).
■More than 70% of patients are diagnosed with advanced disease that is not amenable to curative therapy.
■The 5-year relative survival rate for lung cancer is approximately 18.5%, reflecting a slow but steady improvement from 13.7% in the 1970s.
■Stage at diagnosis accounts for the most marked variation in prognosis. Patient characteristics associated with poorer prognosis include older age, male gender, and African American heritage.
■In the United States, as many women now die from lung cancer as die from breast, uterine, and cervical cancers combined. The increase in lung cancer risk among women reflects changes in smoking habits during the twentieth century. By 1987, lung cancer had surpassed breast cancer as the leading cause of cancer death in women as a result of an increase in the prevalence of female smokers.
■Rates of cigarette smoking have declined in the United States in the last 10 years, but developing nations are now seeing an alarming increase in smoking rates.
ETIOLOGY AND RISK FACTORS
■The vast majority of lung cancer deaths are directly attributable to cigarette smoking.
■Tobacco smoke contains a highly complex mixture of carcinogens that have the potential to damage DNA. Polycyclic aromatic hydrocarbons, aromatic amines, and tobacco-specific nitrosamines have been implicated as the major mutagenic carcinogens responsible for DNA adduct formation. The number of DNA adducts formed is directly related to the number of cigarettes consumed; in heavy smokers they can be responsible for as many as 100 mutations per cell genome.
■Compared to those who have never smoked, smokers have an approximate 20-fold increase in lung cancer risk. The likelihood of developing lung cancer decreases among those who quit smoking compared to those who continue to smoke.
■Estimates indicate that passive smoking accounts for approximately 3,000 lung cancer deaths per year in the United States.
■Radon, a radioactive gas produced by the decay of radium 226, is the second leading cause of lung cancer in the United States, accounting for 6,000 to 36,000 cases of lung cancer each year. The decay of radium 226 produces substances that emit α-particles, which may cause cell damage. Residential exposure has been associated with an increased risk of developing lung cancer.
■Occupational exposure to carcinogens such as asbestos, arsenic, chromates, chloromethyl ethers, nickel, polycyclic aromatic hydrocarbons, and other agents is estimated to cause approximately 9% to 15% of lung cancers. Asbestos exposure in smokers is associated with a synergistic risk of developing lung cancer. Cigarette smoking impairs bronchial clearance and thereby prolongs the presence of asbestos in the pulmonary epithelium.
■The contribution of hereditary factors to the development of lung cancer is less well understood than for any other of the common forms of solid tumors in human. Proof that the familial occurrence of lung cancer has a genetic basis is complicated by the central role of cigarette smoking in the etiology of lung cancer.
■Large randomized, double-blind, placebo-controlled chemoprevention trials reported in the 1990s provided no evidence that specific dietary constituents confer protection against lung cancer.
PATHOLOGY
■NSCLC can be divided into three major subtypes:
•Adenocarcinoma
•Squamous cell carcinoma
•Large cell carcinoma
■Adenocarcinoma is the most frequently diagnosed form of NSCLC in both men and women in the United States. Tumors are classically peripheral and arise from surface epithelium or bronchial mucosal glands. Histologic examination reveals gland formation, papillary structures, or mucin production. The histologic characteristics of lung cancer in several developed countries, including the United States, have changed in the past few decades, demonstrating that the frequency of adenocarcinoma has risen while the frequency of squamous cell carcinoma has declined.
•Bronchioloalveolar carcinoma (BAC), a noninvasive subtype of adenocarcinoma, occurs more frequently in women and nonsmokers, and is associated with bilateral, multifocal pulmonary involvement, a lesser tendency for extrathoracic metastases, and a better survival rate than similar-stage NSCLC.
■A revised multidisciplinary classification of lung adenocarcinoma recommends discontinuing the use of the term BAC and instead introduced new categories such as adenocarcinoma in situ (AIS—small solitary adenocarcinomas with pure lepidic growth) and minimally invasive adenocarcinoma (MIA—small solitary adenocarcinomas with predominant lepidic growth and ≤5 mm invasion).
•Squamous cell carcinoma accounts for approximately 25% of NSCLCs and has the strongest association with cigarette smoking. This tumor arises most frequently in the central proximal bronchi and can lead to bronchial obstruction, with resultant atelectasis or pneumonia. Histologic examination reveals visible keratinization, with prominent desmosomes and intercellular bridges.
■Large cell carcinoma is the least common subtype of lung cancer, accounting for approximately 10% of all NSCLCs.
BIOLOGY
■Lung cancer evolves through a multistep process from normal bronchial epithelium to dysplasia to carcinoma in situ and finally to invasive cancer. These changes include activation of oncogenes, inactivation of tumor suppressor genes, and loss of genomic stability. Changes can be both genetic (via deletions or mutations) and epigenetic (methylation), leading to altered cell proliferation, differentiation, and apoptosis. Mutations in multiple tumor suppressor genes and oncogenes have been associated with the development of NSCLC (Table 2.1). A small subset of somatic mutations (“driver mutations”) are essential for lung carcinogenesis and tumor progression and confer a selective growth advantage to the cancer cell. Cancer cells are often “addicted to” the continued activity of these somatically mutated genes for maintenance of their malignant phenotype.
•p53 is involved in DNA repair, cell division, apoptosis, and growth regulation. In normal conditions, p53 production increases when DNA damage occurs. Increased amounts of p53 induce cell cycle arrest in the G1 phase, allowing DNA repair. If a p53 deletion or mutation exists, G1 arrest is not achieved and the abnormal cell proceeds to S phase, further dividing and propagating genetic damage. Mutations in p53 are found in 50% of NSCLCs.
•The RB gene also regulates G1 growth arrest. Hypermethylation of the CpG-rich island at the 5′ end of the RB gene is thought to lead to silencing of the RB gene and tumor progression. RB gene mutations occur in 15% of NSCLCs.
•The human epidermal growth factor receptor (HER) family are a group of four trans-membrane tyrosine kinase receptors: epidermal growth factor receptor (EGFR, ErbB1, HER1), ErbB2 (HER2/nu or HER2), ErbB3 (HER3), and ErbB4 (HER4). Following binding of a ligand to its extracellular receptor, dimerization occurs, leading to activation of tyrosine kinases and a subsequent increase in downstream signaling pathways including RAS-RAF and AKT protein kinases. These pathways regulate angiogenesis, cell proliferation, and survival. Point mutations within EGFR exons 18 to 21 which encode a portion of the EGFR tyrosine kinase domain predict tumor sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Common EGFR sensitizing mutations include exon 19 deletions and exon 21 L858R point mutations. These mutations are more frequently found in female patients with adenocarcinoma histology, patients of Asian origin, or never or light smokers. They occur in up to 10% of US or European populations and 30% to 50% of Asian patients with NSCLC. Resistance to EGFR TKI may result from acquired mutations, most commonly the EGFR T790M point mutation (50% of cases of acquired resistance), in EGFR tyrosine kinase domain.
•KRAS is a member of the RAS family of oncogenes and codes for a 21-kDa guanine-binding protein that mediates signal transduction pathways from cell surface receptors to intracellular molecules. The RAS–RAF pathway produces signaling downstream of the EGFR trans-membrane tyrosine kinase and promotes survival and proliferation. Mutations in EGFR and KRAS are, in general, mutually exclusive and KRAS mutations confer primary resistance to EGFR TKIs. The RAS oncogene can be activated either by a point mutation or by overexpression. KRAS mutations are found with greater frequency in patients with adenocarcinoma histology (approximately 15% to 30%), Caucasians, and smokers, and are less frequent in Asians.
•The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is aberrant in a variety of malignancies. ALK fusion with a variety of partner genes, most commonly EML4, results in its dimerization and constitutive kinase activity which leads to activation of cellular pathways involved in cell growth and proliferation. Approximately 3% to 7% of NSCLCs harbor ALK fusions. ALK fusions are more common in younger patients, never or light smokers, and patients with adenocarcinoma histology with signet ring or acinar histology and in most cases are mutually exclusive of EGFR and KRAS mutations. ALK fusions predict sensitivity to crizotinib, an ALK/MET TKI.
LUNG CANCER SCREENING
■Randomized trials of screening with chest radiography with or without sputum cytology have shown no reduction in lung cancer–related mortality.
■Low-dose computed tomography (CT) screening may benefit individuals at an increased risk for lung cancer. The potential harms of screening and the generalizability of results are unclear.
•The National Lung Screening Trial (NLST), a randomized trial, compared annual screening by low-dose chest CT scanning with chest x-ray for 3 years in high risk individuals (age between 55 and 74 years with at least 30 pack-year cigarette smoking, and former smokers who had quit within the previous 15 years: n = 53,454). There were 247 deaths from lung cancer per 100,000 person-years in the low-dose CT group and 309 deaths per 100,000 person-years in the radiography group, representing a relative reduction in mortality from lung cancer with low-dose CT screening of 20.0% (95% CI 6.8 to 26.7; P = 0.004). The rate of death from any cause was reduced in the low-dose CT group, compared with the radiography group by 6.7% (95% CI 1.2 to 13.6; P = 0.02).
CLINICAL PRESENTATION
■A minority of patients present with an asymptomatic lesion discovered incidentally on chest radiograph. No set of signs or symptoms are pathognomonic of lung cancer, so diagnosis is usually delayed.
■Clinical signs and symptoms of lung cancer are outlined in Table 2.2.
CLINICAL EVALUATION
Single Pulmonary Nodule
■Definition: Solitary mass, often found incidentally, surrounded by lung tissue, well circumscribed, measures <3 cm without mediastinal or hilar adenopathy.
■Benign inflammatory vascular abnormalities or infectious lesions can mimic more sinister lesions. Review of previous chest imaging is a crucial first step. A stable lesion over a 2-year period suggests a benign condition.
■CT of the chest is required to assess for other nodules, adenopathy, or chest wall invasion.
■18F-fluorodeoxyglucose-positron emission tomography (“FDG-PET”) is used to evaluate single pulmonary nodules (SPNs). False-positive PET scans may occur in conditions such as tuberculosis or histoplasmosis. False-negative results have been reported for small lesions (<1 cm) and neoplasms with low metabolic activity, such as in some cases of BAC. Mean sensitivity of FDG-PET is 96%; mean specificity is 75%. The negative and positive predictive value of PET for pulmonary nodules is approximately 90%.
■A growing SPN needs a pathologic diagnosis. Tissue can be obtained by fine needle aspiration (FNA), transbronchial biopsy, or surgical resection. Flexible fiber optic bronchoscopy is appropriate for central lesions and can lead to a diagnosis in 97% of cases via biopsies, bronchial washings, and brushings.
■Observation may be reasonable in a low-risk individual (<40 years old and has never smoked) with a negative FDG-PET and a stable lesion measuring <2 cm. Reimaging with regular CT scans and follow-up clinic appointments are recommended.
Suspected Lung Cancer
■Full history and physical examination are recommended, followed by complete blood count and chemistry tests, chest x-ray, and CT of the chest and abdomen (including adrenal glands).
■Sputum analysis may be helpful in cases of central lesions.
■Bone scans and plain films of affected areas are warranted where bone pain exists. Routine imaging of the brain in asymptomatic patients is controversial.
■Peripheral lesions may require percutaneous transthoracic FNA, which can be performed under CT or fluoroscopic guidance.
■Mediastinoscopy, a more invasive method, may be needed to obtain a histologic diagnosis in difficult-to-reach primary tumors. Mediastinoscopy can reveal unsuspected tumors in mediastinal lymph nodes—a negative implication for survival. Evaluation of the mediastinum is recommended before surgery in suspected mediastinal disease and intraoperatively prior to any planned resections.
■An accurate pathologic diagnosis and staging of disease is essential in the management of lung cancer. Stage of disease determines whether surgical resection is warranted. Clinical staging often underestimates the true extent of the disease. The combination of PET evaluation and mediastinoscopy is routinely used to complete staging.
■Preresection forced expiratory volume per second (FEV1) should be ≥2 L for pneumonectomy, 1 L for lobectomy, or 0.6 L for segmentectomy.
■Preresection forced vital capacity should be ≥1.7 L.
■In patients who undergo surgical resection, surgical/pathologic staging should be used to predict recurrence and to evaluate the need for adjuvant therapy.
STAGING
■The tumor-node-metastasis (TNM) staging system bases patient prognoses on tumor size, lymph node involvement, and metastasis. Median overall survival for patients with pathologic stages IA, IB, IIA, IIB, IIIA, IIIB, and IV are 119, 81, 49, 31, 22, 13, and 17 months, respectively.
■The seventh edition of the TNM Classification of Malignant Tumours (UICC) was adopted by the American Joint Committee on Cancer (AJCC) in 2010. A summary of the TNM classification, stage grouping, and anatomical drawing can be found at http://www.cancerstaging.org/staging/posters/lung12x15.pdf. In stages I and II, disease is limited to one lung and does not involve the mediastinum or more distant sites. Involvement in stage III is heterogeneous and ranges from a tumor of size ≤ 2 cm with metastasis in ipsilateral mediastinal and/or subcarinal lymph node (T1a, N2-stage IIIA) to a tumor of any size with local invasion or a separate nodule in a different ipsilateral lobe with metastasis in contralateral mediastinal or hilar nodes (T4, N3-stage IIIB). Stage IV includes tumor involvement in a contralateral lobe and presence of malignant pleural (or pericardial) effusions or distant metastases.
TREATMENT
Stages I and II
■Stage I and stage II NSCLCs are considered early-stage disease. These two stages combined account for 25% to 30% of all lung cancers.
■Five-year survival rates are 58% to 73% for stage I and 36% to 46% for stage II.
■Surgical resection is the recommended treatment for patients with stage I and stage II NSCLCs. In patients who are medically fit for surgical resection, lobectomy or greater resection is recommended rather than sublobar resections (wedge or segmentectomy).
■Video-assisted thorascopic surgery (VATS) is an acceptable alternative to open thoracotomy.
■Intraoperative systematic mediastinal lymph node sampling or dissection is recommended for accurate pathologic staging.
■Even with complete resection, approximately half of these patients eventually experience relapse after resection, with a two- to three-fold higher proportion of distant metastases over local recurrences.
•In selected patients who undergo complete surgical resection, several large trials have demonstrated a statistically significant survival benefit from cisplatin-based adjuvant chemotherapy (IALT, ANITA, JBR 10).
•The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis which used individual patient data (n = 4,584) from five trials with a median follow-up of 5.2 years found that adjuvant cisplatin-based chemotherapy was associated with a an decrease in absolute risk of death of 5.4 % at 5 years compared with no chemotherapy (hazard ratio [HR] 0.89; 95% CI 0.82 to 0.96).
■Among completely resected early-stage NSCLC, adjuvant chemotherapy is not recommended for stage IA, is standard for stage II, and may be useful in a subset of patients with stage IB.
•In the LACE meta-analysis, the overall survival benefit varied considerably by stage of disease, with potential harm seen in stage IA (HR 1.40; 95% CI 0.95 to 2.06), a trend toward benefit in stage IB (HR 0.93; 95% CI 0.78 to 1.10), and clear benefit in stage II (HR 0.83; 95% CI 0.73 to 0.95) patients.
■Since there is no reliable way to identify which stage IB patients may derive benefit from adjuvant chemotherapy, current guidelines recommend chemotherapy in stage IB high-risk patients, defined by large size (more than 4 cm), poor differentiation, vascular invasion, visceral involvement, and suboptimal resection.
■Current evidence suggests that postoperative radiotherapy is associated with decreased survival for patients with stage I (N0) and stage II (N1) NSCLCs. However, most meta-analyses included several older studies that used radiotherapy methods that are inferior to current methods.
■If surgery is contraindicated in early-stage NSCLC, radiotherapy can be an effective means of local control. In clinical studies, accelerated radiotherapy (54 Gy in 12 days) was associated with better 4-year survival than conventional radiotherapy (60 Gy in 6 weeks). Stereotactic body radiation therapy (SBRT), which delivers a high dose to a target volume and spares surrounding normal tissues, may be an option for patients with primary tumors of size <5 cm and in whom surgery is contraindicated.
Stage IIIA
■Stage IIIA (N2) NSCLC is a therapeutically challenging and controversial subset of lung cancer, with a 5-year survival rate of only 24%.
■Randomized trials strongly suggest a combined modality approach in stage IIIA disease. Conflicting data, however, have led to difficulties in proposing specific management guidelines. This, in part, is secondary to the heterogeneous nature of stage IIIA disease.
■Clinically N0 or N1 patients are often taken for upfront surgical resection with cure achievable in 25% to 50% of these patients. However, should incidentally discovered N2 disease be found at surgery, complete tumor resection and mediastinal lymphadenectomy are recommended. With the high rate of recurrence in this patient population adjuvant chemotherapy to address micrometastatic disease is recommended.
•The International Adjuvant Lung Cancer Trial of 1,867 patients with stages IB to IIIA (39% stage IIIA) randomized patients to three to four cycles of postoperative cisplatin-based chemotherapy versus surgery alone, with adjuvant 60 Gy radiotherapy given to both arms of stage IIIA patients (the use of radiotherapy was left to the investigator’s choice). After a median 56-month follow-up, the overall survival rate was significantly higher in the chemotherapy group (HR 0.86), with a 5-year survival rate of 44.5% in the chemotherapy group versus 40.4% in the control arm, with the strongest benefit in patients with stage III disease.
•The ANITA study randomized 840 completely resected patients with stages I to IIIA (35% stage IIIA) to four postoperative cycles of cisplatin and navelbine versus observation (radiotherapy as per preference of participating center). After a median follow-up of >70 months, long-term 5-year survival of stage IIIA patients in the chemotherapy arm was significantly greater at 42% versus 26% in the observation arm (P = 0.013).
■Postoperative radiation therapy (PORT), while reducing local recurrence, does not improve survival, may be detrimental, and is not recommended as standard of care. Advocates of radiotherapy have emphasized that there are several differences between the treatment administered in several trials included in this meta-analysis and current practices in the United States.
•The PORT meta-analysis (Meta-Analysis Trialist Group) of 2,128 patients treated in nine randomized trials with a median follow up of 3.9 years found a significant increase in risk of death with PORT (overall risk ratio 1:21; P= 0.001).
■Evidence has yet to be established substantiating the benefit of adding adjuvant radiotherapy to adjuvant chemotherapy in fully resected stage IIIA patients.
■Individuals with clinically apparent (bulky) N2 disease or N2 disease found at mediastinoscopy prior to thoracotomy should not undergo upfront surgery based on the poor results of primary resection for bulky stage IIIA disease. Selected patients with nonbulky N2 disease, defined as a single N2 positive node less than 2 cm, may be considered for surgical resection followed by adjuvant therapy. However, thorough discussion regarding lack of data illustrating optimal treatment in this setting is needed.
■Poor survival rates with surgery alone in N2 disease, even with postoperative chemotherapy or radiotherapy, have led to the use of radiotherapy and/or chemotherapy in the neoadjuvant setting, with the aim of making an unresectable tumor resectable and improving long-term survival. Theoretically, advantages include shrinking the tumor to allow for easier resection and nodal clearance, decreased surgical seeding, in vivo chemosensitivity testing of the chemotherapy regimen, and increased patient acceptance and compliance. Disadvantages of neoadjuvant therapy may include delayed tumor resection and increased surgical morbidity and mortality. While high rates of pathologic complete response and negative mediastinal nodes result from neoadjuvant chemoradiotherapy, it is also associated with substantial toxicity.
•A meta-analysis evaluating neoadjuvant chemotherapy found a nonstatistically significant trend in favor of neoadjuvant chemotherapy (HR 0.65; 95% CI 0.41 to 1.04).
•Two clinical trials (European Organization for Research and Treatment of Cancer 08941 and North American Intergroup 0196) showed no significant difference in overall survival between patients with bulky stage IIIA NSCLC treated with neoadjuvant chemotherapy then surgery versus definitive chemoradiation alone (no surgery).
■The use of concurrent chemotherapy/radiotherapy versus sequential treatment has been addressed in numerous trials. At present, for patients with bulky N2 disease treatment with concurrent over sequential chemotherapy/radiotherapy is recommended.
■Concurrent chemotherapy/radiotherapy followed by consolidation chemotherapy is currently not recommended as standard of care.
Stage IIIB
■All patients with N3 (metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular node) involvement or T4 N2 disease are stage IIIB. Anticipated 5-year survival for most patients with stage IIIB disease is 3% to 7%.
■Optimal treatment depends on extent of disease, age of patient, comorbidities, performance status (PS), and weight loss.
■Stage IIIB lung cancers are not amenable to curative surgical resection unless they are highly selected.
■For patients with stage IIIB disease with PS of 0 to 1, and minimal weight loss (<5%), platinum-based combination chemoradiotherapy followed by chemotherapy is recommended.
■The most common chemotherapeutic agents used concurrently with radiotherapy are etoposide, vinblastine, and paclitaxel in conjunction with cisplatin or carboplatin. No randomized phase III trials of concurrent chemoradiotherapy have shown the superiority of one chemotherapy regimen over another.
■Studies have shown that induction chemotherapy followed by concurrent chemoradiotherapy is not superior to initial treatment with concurrent therapy. It is uncertain how many cycles of chemotherapy are optimal in the treatment of patients with stage IIIB disease. The American Society of Clinical Oncology (ASCO) guidelines recommend two to four cycles of platinum-based chemotherapy, two of which should be administered concurrently with thoracic radiotherapy.
Stage IV or Recurrent Disease
■Prognosis for patients with advanced-stage NSCLC is poor. Best supportive care produces median survival rates of 16 to 17 weeks and 1-year survival rates of 10% to 15%. Addition of chemotherapy improves 1-year survival to >35%.
■Subsets of patients with stage IIIB disease who are treated as though they have stage IV disease include those with advanced ipsilateral supraclavicular adenopathy, and those whose intrathoracic disease is not amenable to combined treatment modalities.
■Therapy options for patients with advanced or metastatic disease includes chemotherapy or targeted therapy as these are shown to improve quality of life and reduce symptoms from disease burden. However, chemotherapy is only palliative in nature, and not curative, therefore supportive therapy alone may be chosen if the patient is unable to tolerate systemic treatments due to poor PS or other comorbidities.
■Chemotherapeutic regimens can be divided into first-line, maintenance, second-line, and third-line settings.
First-Line Therapy
■Several factors have to be considered in choice of first-line treatment for metastatic or recurrent NSCLC: age, PS, and comorbidities of the patient, and molecular abnormalities and histology of the tumor.
■Patients with tumors harboring EGFR-sensitizing mutations should receive an EGFR TKI. In such patients, several studies have shown the efficacy of erlotinib and gefitinib, oral small molecule inhibitors which compete with ATP for binding to the EGFR receptor tyrosine-kinase domain.
•The IPASS trial which randomized previously untreated patients with NSCLC who were likely to have EGFR mutations based on clinical criteria (n = 1,217) (Asian, adenocarcinoma histology, never or former light smokers) to receive gefi tinib (250 mg PO qd) or chemotherapy found superior response rates (43.0% vs. 32.2%) and PFS (12-month progression-free rate 25 vs. 7%) with gefitinib. The most common adverse reactions with EGFR TKIs are skin rash and diarrhea.
■Patients with tumors harboring ALK translocations, as detected by an approved ALK break-apart fluorescence in situ hybridization FISH test, should receive crizotinib, an oral selective small molecule inhibitor of the catalytic activity of ALK fusion protein among others.
•In an expanded cohort phase I trial, crizotinib resulted in overall response rates of over 50% in previously treated patients with advanced NSCLC positive for ALK translocation.
■Patients harboring neither EGFR mutations nor ALK translocation should receive standard chemotherapy. Four to six cycles of platinum-based doublets prolongs survival and improves symptom control and is the standard of care for patients with recurrent or metastatic NSCLC and good PS. However, no single regimen has demonstrated superiority in patients with advanced NSCLC and treatment decisions should be based on benefit versus toxicity.
•An ECOG study which randomized 1,207 patients to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel found comparable efficacy for all four regimens. This trial yielded an objective response rate of 19%, with a median survival of 7.9 months, a 1-year survival rate of 33%, and a 2-year survival rate of 11%.
■Histology is an important determinant of the choice of chemotherapy agent. A phase III trial comparing pemetrexed/cisplatin to cisplatin/gemcitabine in 1,700 advanced/metastatic patients in the first-line setting found OS between both treatment arms to be the same. However, subset analysis for histology revealed significant differences.
•In patients with adenocarcinoma histology, combination of pemetrexed with cisplatin demonstrated improved survival and reduced toxicity compared with gemcitabine/cisplatin. OS was 12.6 months in the pemetrexed arm versus 10.9 months in the gemcitabine arm.
•Conversely those with squamous histology showed improved survival with cisplatin/gemcitabine (10.8 months) as initial chemotherapy treatment versus pemetrexed/cisplatin (9.4 months).
■Bevacizumab, a recombinant humanized monoclonal antibody that is directed against VEGF (thereby preventing its interaction with the VEGF receptor), is approved for treatment of nonsquamous histology advanced/metastatic disease in combination with chemotherapy as first-line treatment.
•ECOG 4599 which randomized selected patients with nonsquamous NSCLC (n = 878) to chemotherapy (carboplatin/paclitaxel) alone or with bevacizumab found significant improvements in OS (median 12.3 vs. 10.3 months), PFS (median 6.2 vs. 4.5 months) and response rates (35% vs. 15%). The risk of treatment-related deaths was higher in patients who received bevacizumab.
•The AVAiL trial further evaluated bevacizumab in nonsquamous histology tumors randomizing patients to cisplatin/gemcitabine with our without two different doses of bevacizumab. Although addition of bevacizumab significantly prolonged PFS, the improvement was modest (median 6.7 and 6.5 months respectively for bevacizumab 7.5 mg/kg and 15 mg/kg respectively; 6.1 months for placebo), and there was no OS benefit with addition of bevacizumab. It is unclear whether the lack of OS benefit is secondary to differences in chemotherapy between the two trials.
■Cetuximab is a monoclonal antibody that binds to the EGFR. It may be considered only for highly selected patients with PS of 0 to 1.
•The phase III FLEX trial randomized patients with EGFR-expressing advanced NSCLC to cetuximab plus cisplatin/vinorelbine versus cisplatin/vinorelbine alone. Patients received a maximum of 6 cycles every 3 weeks. Cetuximab was administered until progression or unacceptable toxicity. A small, yet significant OS benefit, regardless of histology, was seen: median OS of 11.3 months for cetuximab arm versus 10.1 months in the control arm.
•Cetuximab was further evaluated in the first-line setting in the BMS099 trial comparing paclitaxel or docetaxel plus carboplatin with randomization to receive cetuximab versus placebo, which was continued until disease progression or unacceptable toxicity. No differences in response, PFS, or OS were seen.
■Addition of a third chemotherapeutic agent to platinum-based doublets has failed to show a superior survival benefit; response rates improved only at the cost of substantially increased toxicity.
Maintenance Chemotherapy
■Maintenance therapy is the use of systemic therapy in patients with a response or stable disease after first-line therapy until disease progression or unacceptable toxicity with goals of delaying disease progression and to extend survival, without adversely affecting quality of life.
■One of the drugs used in first-line therapy (continuation maintenance) or a new agent (switch maintenance) may be used for maintenance.
■Pemetrexed, bevacizumab, gemcitabine, or cetuximab may all be chosen as continuation maintenance options.
•The PARAMOUNT trial, a double-blind placebo-controlled trial which investigated continuation pemetrexed maintenance therapy in patients with nonsquamous histology, found that pemetrexed maintenance resulted in a 36% reduction in risk of progression (HR 0.64; 95% CI 0.51 to 0.81; P = 0.00025).
•The phase III, IFCT-GFPC 0502 trial randomized patients to maintenance gemcitabine, erlotinib, or observation after lack of progression on cisplatin/gemitabine as upfront therapy. A significant improvement in PFS was observed for the gemcitabine maintenance (HR 0.51; 95% CI 0.39 to 0.66). Gemcitabine may be used in patients with squamous histology for continuation maintenance.
•Both cetuximab (FLEX trial) and bevacizumab (ECOG 4599) (discussed above) demonstrated PFS benefit to the continuation of these therapies after nonprogression on upfront chemotherapy. Cetuximab may be used as continuation maintenance in patients with squamous cell histology unlike bevacizumab.
■Pemetrexed, docetaxel, and erlotinib are chemotherapeutic options for switch maintenance therapy.
•A phase III study evaluated the use of pemetrexed maintenance following nonprogression with nonpemetrexed–containing platinum-based chemotherapy versus best supportive care. Pemetrexed significantly improved not only PFS (4.3 vs. 2.6 months; HR 0.5; 95% CI 0.42 to 0.61; P < 0.0001) but also OS (13.4 vs. 10.6 months; HR 0.79; 95% CI 0.65 to 0.95; P = 0.012) compared to placebo, respectively.
•Erlotinib switch maintenance has been studied after nonprogression on platinum-based chemotherapy. PFS was significantly longer for the erlotinib arm compared to placebo, regardless of EGFR mutational status (12.3 vs. 11.1 weeks; P < 0.0001). However, patients with EGFR mutations were the ones who benefited the most from maintenance erlotinib.
•In patients with squamous histology docetaxel maintenance may be considered.
■Maintenance chemotherapy may be ideal in patients where close monitoring for disease progression is not feasible and for whom rapid disease progression after the completion of first-line treatment may preclude administration of active second-line agents.
Second-Line Therapy
■Most patients who undergo first-line therapy will eventually develop disease progression and second-line therapy is administered in this setting.
■Second-line therapy has an impact on survival and quality of life in advanced NSCLC; therefore, patients with a PS of 0 to 2 should be offered further treatment following progression.
■Approved agents for treatment of locally advanced or metastatic NSCLC after one prior therapy are docetaxel, pemetrexed (in nonsquamous histology), and erlotinib.
•TAX 317, a phase III trial which randomized patients with advanced NSCLC and prior platinum-based chemotherapy (n = 104) to docetaxel (75 mg/m2 IV every 21 days) or best supportive care, found longer overall survival with docetaxel (median 7.5 months vs. 4.6 months).
•In an open-label randomized phase III trial of patients with advanced NSCLC after failure of one chemotherapy regimen (n = 571), pemetrexed (500 mg/m2 IV every 21 days) resulted in equivalent efficacy outcomes with docetaxel (median OS 8.3 months vs. 7.9 months for docetaxel) but with significantly fewer side effects.
•BR 21, a randomized (2:1), double blind, placebo-controlled trial of patients advanced NSCLC after failure of one or two chemotherapy regimens (n = 731), demonstrated improved OS with erlotinib (150 mg PO qd) (6.7 months vs. 4.3 months for placebo).
Third-Line Therapy
■Erlotinib is also an approved agent in the third-line setting. If disease progression occurs after second-line or third-line chemotherapy, it is recommended that patients with a PS of 0 to 2 be enrolled in a clinical trial or treated with best supportive care.
REVIEW QUESTIONS
1.A 70-year-old otherwise healthy former smoker presents with persistent cough and hemoptysis of 2-month duration. Further workup reveals a 3 cm cavitating hilar mass, multiple bilateral parenchymal lung nodules, and a 2 cm hypodense lesion in the right hepatic lobe. Biopsies of the lung and liver masses are consistent with squamous cell lung carcinoma. Tumor molecular analysis shows the absence of EGFR, KRAS mutations, and ALK fusion. MRI brain shows no evidence of metastatic disease. Which of the following combinations would be the best choice for first-line chemotherapy?
A.Cisplatin and gemcitabine
B.Cisplatin and pemetrexed
C.Carboplatin, paclitaxel, and bevacizumab
D.Carboplatin, pemetrexed, and bevacizumab
2.Based on available data, which of the following is true regarding screening for lung cancer in a 54-year-old man with 20 pack-year history of smoking who quit 3 years ago?
A.Annual low-dose CT screening is expected to result in a reduction in lung cancer–related mortality
B.Annual low-dose CT screening is expected to result in a reduction in all-cause mortality
C.Chest x-ray and sputum cytology are expected to result in a reduction in lung cancer–related mortality
D.Chest x-ray and sputum cytology are expected to result in a reduction in all-cause mortality
E.None of the above
3.A 70-year-old otherwise healthy woman came to medical attention with long-standing cough. CT scan showed a 4 cm left hilar mass and right hilar lymphadenopathy. The patient underwent bronchoscopy, right video-assisted thoracic surgery, wedge biopsy, and cervical mediastinoscopy with biopsy. Pathology showed lung adenocarcinoma with involvement of right hilar lymph nodes. Tissue is inadequate for molecular analyses. Which of the following is the best treatment option?
A.Surgical resection of the primary mass and lymph nodes followed by adjuvant chemoradiation
B.Concurrent chemotherapy and radiation
C.Neoadjuvant chemotherapy followed by surgery
D.Sequential chemotherapy and radiation
Suggested Readings
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