Ali Mohamed • Saiama N. Waqar
I. NON–SMALL CELL LUNG CANCER
Patients may present with laboratory abnormalities such as anemia due to chronic disease, hypercalcemia as part of a paraneoplastic syndrome, hyponatremia due to syndrome of inappropriate antidiuretic hormone syndrome, and elevated transaminases or hyperbilirubinemia due to liver metastasis. There are no reliable or clinically useful serum tumor markers for diagnosis or follow-up of lung cancer, though carcinoembryonic antigen (CEA) may be elevated in some patients.
Mediastinoscopy is very useful in determining the status of mediastinal lymph nodes in patients who are considered to be candidates for surgical resection. Evaluation of mediastinal lymph nodes by mediastinoscopy is critical before surgical resection. Normal-appearing mediastinal lymph nodes may contain metastatic disease, and sometimes enlarged lymph nodes in the mediastinum may represent only hyperplastic lymph nodes from postobstructive pneumonia or may represent old granulomatous infection. Cervical mediastinoscopy is more accurate for staging superior mediastinal lymph nodes, whereas extended or anterior (Chamberlain) approach is better for anterior mediastinal lymph nodes. Endoscopic and endobronchial ultrasonography are being increasingly utilized to biopsy the mediastinal lymph glands. Many thoracic surgeons do not perform preoperative mediastinoscopy if the CT chest and FDG PET reveal no abnormalities in the mediastinum.
Video-assisted thoracoscopic surgery (VATS) can be used to access peripheral nodules, suspected pleural disease, and effusions.
Definitive radiation therapy (RT) is an alternative for patients who are not candidates for surgery. Selection of patients for RT is based largely on the extent of the primary tumor and the prognostic factors. On the basis of retrospective data, the patterns of failure following surgery (lobectomy/pneumonectomy) or stereotactic body radiation therapy (SBRT) are comparable (J Thorac Oncol 2013;2:192). Survival after RT depends on the patient’s overall health status, radiation dose, tumor size, and complete response by 6 months after completion of RT.
Preoperative RT is not considered appropriate in early-stage lung cancer. The role of postoperative radiotherapy (PORT) was evaluated in the PORT meta-analysis, which was a pooled analysis of 2,128 patients with lung cancer treated in nine randomized trials between 1966 and 1994, and demonstrated a 7% absolute reduction in 2-year overall survival, with the greatest detrimental effect in patients with stage I disease. In patients with Nl or N2 disease, two studies by the Lung Cancer Study Group (LCSG) and the British Medical Research Council (BMRC) concluded that PORT could improve local control but did not affect overall survival, possibly because of lack of effect on systemic disease. PORT is not recommended for patients with N0 or N1 disease, but may have some benefit in patients with N2 disease who are medically fit, and for patients with positive surgical margins.
Adjuvant chemotherapy was not standard of care until the last decade, since older adjuvant chemotherapy regimens studied did not show a survival benefit. From 1996 to 2005, a series of randomized studies of adjuvant chemotherapy in NSCLC were performed, using platinum doublets and triplets. An absolute 5-year survival benefit of 5.4% with adjuvant chemotherapy was found in a pooled analysis by the LACE collaborative group. This analysis included the five largest clinical trials that used adjuvant cisplatin-based chemotherapy after surgical resection [International Adjuvant Lung Cancer Trial (IALT), intergroup JBR.10 trial, Adjuvant Navelbine International Trialists Association (ANITA), European Big Lung trial, and the Adjuvant Lung Project Italy (ALPI)]. The survival benefit from adjuvant chemotherapy was greatest with the regimen of cisplatin and vinorelbine, with the most significant effect seen in patients with stage II and III NSCLC. Adjuvant chemotherapy should be considered for patients with stage II and III disease. The role of adjuvant chemotherapy in stage IB disease is controversial. American Society for Clinical Oncology (ASCO) and National Comprehensive Cancer Network (NCCN) recommended careful consideration for adjuvant chemotherapy in stage IB rather than routine use. So far, no prospective studies have demonstrated overall improvement in survival with molecularly targeted therapies in patients with completely resected NSCLC. The ongoing ALCHEMIST study, an NCI-sponsored study, will evaluate the benefit of adding molecularly targeted therapies in this setting in molecularly defined subgroups.
Among patients with stage IIIA, surgery is the standard therapy for those with T3N1, followed by adjuvant chemotherapy, whereas the role of surgery is controversial for patients with stage IIIAN2, with no survival improvement from surgery after chemoradiotherapy in two large studies, the Intergroup 0139 and the European Organization for Research and Treatment of Cancer (EORTC) 08941. At present, definitive chemoradiation is considered standard of care for patients with T4, N2, or N3 involvement. When mediastinal involvement is detected only at the time of resection, surgery should be followed by adjuvant chemotherapy with or without sequential RT. Patients with superior sulcus syndrome without mediastinal lymph gland involvement or disease involving the spine are candidates for surgery following induction chemoradiation.
RT alone is not an optimal therapy in patients with unresectable stage III NSCLC and good PS, as the 5-year survival rates are only 5%.
It has been shown that the addition of chemotherapy to RT improves survival in patients with stage III NSCLC over RT alone. Chemotherapy administered concurrent with radiation is superior to induction chemotherapy followed by sequential thoracic radiation, due to improved survival, though at the cost of increased toxicity with increased incidence of acute esophagitis and pneumonitis. Common regimens in use include cisplatin and etoposide concurrent with radiation and carboplatin and paclitaxel concurrent with thoracic radiation. The role of consolidation chemotherapy with docetaxel was evaluated by the HOG-LUN 01-24 trial, where three cycles of docetaxel versus observation were given after concurrent chemoradiation using cisplatin and etoposide with thoracic radiation to 59.4 Gy (1.8 Gy/fraction). The updated results showed no significant difference in survival between the two groups, but more toxicities on the docetaxel arm (Ann Oncol 2012;23:1730–1738). Currently, concurrent chemoradiation with cisplatin-based doublet is recommended in patients with good PS and unresectable stage III disease. Although consolidation chemotherapy (chemotherapy after chemoradiotherapy) is commonly used, it has not been shown to improve outcomes in randomized clinical trials. For patients with poor PS, thoracic radiation alone or sequential chemotherapy followed by radiation are administered for symptom palliation and survival prolongation. Given the high incidence of eventual brain metastasis in patients with stage III disease, the role of prophylactic cranial irradiation (PCI) has been examined in this patient population. Although PCI resulted in decreased incidence of brain metastasis, there was no survival benefit from PCI in these patients. The RTOG 1306 study is examining the role of induction-targeted therapy followed by chemoradiotherapy in patients with locally advanced NSCLC.
i. EGFR. Initial studies with first generation reversible EGFR tyrosine kinase inhibitors (gefitinib and erlotinib) were conducted in molecularly unselected patients with previously treated NSCLC. The response rates for gefitinib were 11% and 18%, respectively, in the two Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL) trials. However, gefitinib was not found to improve survival compared with placebo in the Iressa Survival Evaluation in Lung Cancer (ISEL) study. Erlotinib, another EGFR TKI, was found to improve both PFS and OS compared with placebo in the BR.21 study, and was approved by the U.S. Food and Drug Administration (FDA) in previously treated molecularly unselected patients, based on the results of this study. Clinical predictors for response to EGFR TKI include adenocarcinoma histology, female gender, East Asian ethnicity, and never smoker or previous light smoker status. Presence of activating EGFR tyrosine kinase mutations in the tumor, including deletion in exon 19 and L858R mutation involving exon 21 render the receptor constitutively active and predict for response to EGFR TKI therapy.
Gefitinib was the first EGFR TKI to be compared with chemotherapy in the frontline setting in light or never smokers in the Iressa Pan Asia Study (IPASS). Subset analysis confirmed improved response rates (71.2% vs. 47.3%) and significant progression-free survival advantage in patients with EGFR mutations (mainly exon 19 deletion or the exon 21 L858R mutation) who were treated with gefitinib compared with chemotherapy (J Clin Oncol 2011;29:2866). The OPTIMAL and EURTAC trials confirmed the progression-free survival and objective response rate advantages of erlotinib (EGFR TKI) in EGFR-mutant patients. Afatinib is a second-generation irreversible EGFR inhibitor that also targets HER2 and HER4 and was recently approved by the FDA for treatment of patients with activating EGFR tyrosine kinase mutations, based on the results of the phase III Lux-Lung 3 trial. In this study, afatinib was compared with cisplatin and pemetrexed in the frontline setting and was associated with significant improvement in PFS (11.1 vs. 6.9 months; HR 0.58, p=0.001) (J Clin Oncol 2013;31:3327). Most recently, it has been shown that this effect was specifically more pronounced in the subset of patients with exon 19 deletions.
However, despite the initial response, virtually all patients with EGFR-mutant NSCLC eventually develop disease progression on EGFR TKI therapy. Mechanisms of secondary resistance include EGFR T790M mutation (50% of patients), PIK3CA mutations, and gene amplifications of MET and HER2. Studies of third-generation EGFR TKIs (AZD 9291 and CO 1686) designed to target the T790M mutation have shown very promising results so far.
ii. Anaplastic lymphoma kinase (ALK) gene rearrangements. EML4-ALK is a novel fusion gene that is present in 3% of patients with advanced NSCLC. Additional partners of ALK fusion that have been described include TGF, KIF5B, and KLC1. ALK gene fusions are more commonly seen in younger patients with adenocarcinoma histology who report no history of tobacco smoking and have wild-type EGFR.
Crizotinib produces an impressive response rate of 57% in patients with ALK FISH–positive tumors. In a randomized second-line clinical trial comparing crizotinib with docetaxel or pemetrexed in ALK-positive patients, crizotinib was associated with a significant improvement in median PFS (7.7 vs. 3 months; HR 0.49, p < 0.001). Among the patients randomized to chemotherapy in this trial, pemetrexed was associated with improved PFS compared with docetaxel (4.2 vs. 2.6 months) (N Engl J Med 2013;368:2385). Crizotinib is currently being compared to chemotherapy with platinum plus pemetrexed in patients with ALK-positive tumors, in the frontline setting.
Resistance mechanisms to ALK inhibitors can be categorized as ALK-dominant, due to an ALK-resistant mutation or ALK copy number gain, or ALK-nondominant due to a second oncogene. Ceritinib is a selective oral tyrosine kinase inhibitor of ALK, which is 20 times as potent as crizotinib in inhibiting ALK. Ceritinib has activity both in patients who are ALK-inhibitor naïve (Overall Response Rate, ORR 70%) and in patients who have received prior ALK-inhibitor treatment (ORR 55%). Ceritinib crosses the blood–brain barrier and may be a good option for patients with brain metastasis, with ORR of 54% in target brain lesions. In view of the impressive ORR, ceritinib received accelerated approval by the FDA. Several novel ALK inhibitors are in development.
iii. Other targetable molecular alterations in NSCLC. ROS1 gene rearrangements are seen in 2% of patients with lung adenocarcinoma, and are also observed more commonly in never smokers. Crizotinib is an inhibitor of ROS1, in addition to MET and ALK. The response rate to crizotinib in patients whose tumors carry ROS1 gene fusions is 57%. KIF5B-RET gene fusion occurs in 1% of lung adenocarcinomas and represents novel targets in lung adenocarcinoma. Patients whose tumors carry RET gene fusions tend to be never smokers and younger, with small poorly differentiated primary tumors with N2 nodal involvement. A phase II study of cabozantinib, an inhibitor of RET tyrosine kinase activity, is ongoing. In the preliminary report of the first three patients enrolled, two patients had partial response (PR) and the third had stable disease.
BRAF mutations are also seen in 2% of lung adenocarcinomas, with half of them comprising of BRAF V600E mutations, while the remainder are characterized as non-V600E mutations. The response to BRAF inhibitor dabrafenib in patients with BRAF V600E mutations is 40% based on preliminary data from the BRF113928 study.
HER2 mutations involving exon 20 occur in 1% to 2% of patients with NSCLC. These mutations tend to occur in never smokers, and mostly in women. Afatinib, an inhibitor of HER1, HER2, and HER4 is associated with 100% disease control rate in a four-patient case series of HER2 mutation–positive lung adenocarcinoma, while trastuzumab-based therapies resulted in 96% disease control rate in 15 patients. The largest study of patients with HER2 mutation–positive patients with lung cancer is ongoing, in which patients are being treated with neratinib, an inhibitor of HER2, in combination with temsirolimus, an inhibitor of mTOR.
KRAS mutations are the most frequently observed somatic molecular alterations in lung adenocarcinoma (30%), occurring mostly in codons 12 and 13. KRAS mutations have proven difficult to target. The Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial included 14 patients with mutations in either BRAF or KRAS treated with sorafenib, with a disease control rate of 79%. A phase II study randomized patients with KRAS-mutant NSCLC to receive second-line docetaxel alone versus docetaxel in combination with selumetinib, an inhibitor of MEK. The selumetinib had an improved response rate (16%) compared with the docetaxel arm (0%), but the study failed to meet its primary end point of improvement in OS with addition of selumetinib to docetaxel.
i. Atelectatic lobe, especially in COPD patients. Re-expansion is expected in 60% to 70% of patients if atelectasis has been present for less than 2 weeks.
ii. Hemoptysis, intractable cough, and pain.
iii. Metastatic disease. Bone: RT is used to alleviate pain and prevent impending fracture or compression syndrome. In case of pathologic fracture, RT is used in conjunction with orthopedic fixation to maintain function and activity. Brain: for solitary brain metastasis, better survival and function is seen when the lesion is resected before RT.
The typical radiographic appearance of SCLC is small primary tumors with large hilar and mediastinal lymph node involvement. Pleural effusions occur less frequently, though if present, upstage the patient to the “extensive stage” category.
Staging for SCLC includes a CT scan of the chest and abdomen with contrast, to evaluate for primary tumor, nodal metastasis, and metastasis to liver and adrenal glands. Given the high propensity for brain metastasis in these patients, brain imaging (CT with contrast or brain MRI) should be performed for all patients at presentation. When distant metastasis is not apparent on these imaging studies, a PET scan should be performed. PET scans have been shown to upstage limited stage–SCLC to extensive stage–SCLC in up to 19% of patients (Cancer Imaging 2012;11:253).
i. Chemotherapy. Although patients with SCLC respond to chemotherapy initially, almost all will relapse and die from the disease. Combination chemotherapy results in higher response rates and longer survival than does single-agent chemotherapy. The overall response rate to treatment for limited-stage SCLC is estimated to be 80% to 90%. The combination of cisplatin and etoposide (PE) has been repeatedly demonstrated to yield similar or improved results as compared with any other studied combination, and is easily one of the most commonly used chemotherapeutic regimens for patients with SCLC. In addition, this combination is tolerated well when administered in conjunction with thoracic radiation. We typically administer PE for four to six cycles for those patients who have no evidence of progressive disease. A meta-analysis indicated that carboplatin can replace cisplatin without differences in outcome (J Clin Oncol 2012;30:1692).
ii. RT. Administration of thoracic RT in conjunction with systemic chemotherapy has been shown to improve survival. A meta-analysis of 13 trials including 2,140 patients with limited disease demonstrated a higher survival rate for combined-modality approach with the combination of chemotherapy and thoracic RT as compared with combination chemotherapy alone, with the 3-year survival increasing from 8.9% to 14.3% (N Engl J Med 1992;327:1618). The intergroup 0096 study demonstrated improved survival with 1.5 Gy twice daily thoracic radiation to a dose of 45 Gy in 3 weeks, compared with 1.8 Gy once daily radiation to a total dose of 45Gy in 5 weeks (26% vs. 16%) (N Engl J Med 1999;340:265). The schedule of RT and temporal coordination with chemotherapy may be of some importance, with early RT associated with improved survival compared with treatment starting at the third or fourth cycles of chemotherapy (J Clin Oncol 2004;22:4785).
iii. PCI. For those limited-stage patients who demonstrate a complete response to induction chemotherapy, PCI should be considered to reduce the incidence of brain metastasis and improve survival. A meta-analysis of 987 patients demonstrated a 16% decrease in mortality, 5.4% increase in 3-year survival, decreased incidence of brain metastasis, and prolonged disease-free survival in limited-stage patients who received PCI after complete response to induction chemotherapy (N Engl J Med 1999;341:476). The EORTC 08993 randomized 286 patients with any response to induction chemotherapy to PCI or observation. PCI was associated with improved 1-year overall survival from 13.3% to 27.1% (N Engl J Med 2007;357:664). Late neurocognitive dysfunction may develop, and careful consideration is imperative when treatment is offered to the elderly and patients with poor PS. Administering PCI after chemoradiation and in low doses per fractions could further reduce the risk of neurologic sequelae.
Although the JCOG 9511 study showed improved survival from the combination of cisplatin and irinotecan compared with PE, confirmatory studies in the United States showed no difference in outcomes from the two regimens (Cancer 2010;116:5710).
i. Relapsed SCLC. In spite of a high response rate, most patients with SCLC eventually have relapse of the disease and die of progressive disease. There are two categories of relapsed SCLC: sensitive relapse, that is, those who relapse 3 months after the completion of therapy, and resistant relapse, that is, those who have progressive disease during initial chemotherapy or those who have relapse within 3 months of completion of therapy. Although the response rates for the subgroup of patients with sensitive relapse is approximately 25%, fewer than 10% of patients with resistant relapse respond to salvage therapy. A number of single agents have been reported to be active in this setting including irinotecan (16% to 47%), paclitaxel (29%), docetaxel (25%), oral etoposide (23%), gemcitabine (6% to 16%), vinorelbine (15%), and temozolomide (16%). Topotecan is the only approved regimen for salvage chemotherapy in sensitive relapse patients. A phase III trial comparing topotecan with cyclophosphamide, adriamycin, and vincristine (CAV) reported similar survival and response rates, but lesser toxicity with topotecan (J Clin Oncol 1999;17:658). A randomized study comparing oral and intravenous topotecan showed similar outcomes, with median overall survivals of 33 and 35 weeks, respectively (J Clin Oncol 2006;25:2086).
The natural history of the progression of this disease is that of rapid growth and early dissemination. The median survival of patients with limited-stage SCLC is 15 to 20 months. The reported 5-year survival varies from 10% to 13%. Median survival in extensive stage is 8 to 13 months, but only 2 to 4 months if untreated. From 50% to 80% of patients who survive longer than 2 years will have metastases to the brain.
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