TREATMENT: Non–Small Cell Lung Cancer
The overall treatment approach to patients with NSCLC is shown in Fig. 35-4.
MANAGEMENT OF OCCULT AND STAGE 0 CARCINOMAS Patients with severe atypia on sputum cytology have an increased risk of developing lung cancer compared with those without atypia. In the uncommon circumstance where malignant cells are identified in a sputum or bronchial washing specimen but the chest imaging appears normal (TX tumor stage), the lesion must be localized. More than 90% of tumors can be localized by meticulous examination of the bronchial tree with a fiberoptic bronchoscope under general anesthesia and collection of a series of differential brushings and biopsies. Surgical resection following bronchoscopic localization improves survival compared with no treatment. Close follow-up of these patients is indicated because of the high incidence of second primary lung cancers (5% per patient per year).
SOLITARY PULMONARY NODULE AND "GROUND-GLASS" OPACITIES A solitary pulmonary nodule is defined as an x-ray density completely surrounded by normal aerated lung with circumscribed margins, of any shape, usually 1–6 cm at greatest diameter. The approach to a patient with a solitary pulmonary nodule is based on an estimate of the probability of cancer, determined according to the patient's smoking history, age, and characteristics on imaging (Table 35-7). Prior chest radiographs and CT scans should be obtained if available for comparison. A PET scan may be useful if the lesion is greater than 7–8 mm in diameter. If no diagnosis is apparent, Mayo Clinic investigators reported that clinical characteristics (age, cigarette smoking status, and prior cancer diagnosis) and three radiologic characteristics (nodule diameter, spiculation, and upper lobe location) were independent predictors of malignancy. At present, only two radiographic criteria are thought to predict the benign nature of a solitary pulmonary nodule: lack of growth over a period >2 years and certain characteristic patterns of calcification. Calcification alone, however, does not exclude malignancy; a dense central nidus, multiple punctate foci, and "bull's-eye" (granuloma) and "popcorn ball" (hamartoma) calcifications are highly suggestive of a benign lesion. In contrast, a relatively large lesion, lack of or asymmetric calcification, chest symptoms, associated atelectasis, pneumonitis, or growth of the lesion revealed by comparison with an old radiograph or CT scan or a positive PET scan are suggestive of a malignant process and warrant further attempts to establish a histologic diagnosis. An algorithm for assessing these lesions is shown in Fig. 35-3.
Since the advent of screening CTs, small GGOs have often been observed, particularly as the increased sensitivity of CTs enables detection of smaller lesions. Many of these GGOs, when biopsied, are found to be BAC. Some of the GGOs are semiopaque and referred to as "partial" GGOs. These are often more slow-growing and harbor atypical adenomatous hyperplasia histology and are thought to be precursors to adenocarcinoma. By contrast, "solid" GGOs have faster growth rates and are usually typical adenocarcinoma histologically.
MANAGEMENT OF STAGES I AND II NSCLC
Surgical Resection for Stages I and II NSCLC Surgical resection by an experienced surgeon is the treatment of choice for patients with clinical stage I or II NSCLC who are able to tolerate the procedure. A retrospective review indicated that operative mortality rates for patients whose tumors were resected by noncardiothoracic or cardiothoracic surgeons were lower compared with general surgeons (5.8% vs 5.6% vs 7.6%; P = .001). The extent of resection is a matter of surgical judgment based on findings at exploration. A clinical trial in patients with stage IA NSCLC found that lobectomy was superior to wedge resection in reducing the rate of local recurrence, with a trend toward improvement in overall survival. A retrospective review of the Surveillance, Epidemiology, and End Results (SEER) database also reported a survival benefit for lobectomy compared with wedge resection. A limited resection, wedge resection, and segmentectomy (potentially by video-assisted thoracic surgery [VATS]) may be more appropriate in patients with comorbidities, including compromised pulmonary reserve and small peripheral lesions. Pneumonectomy is reserved for patients with very central tumors and should only be performed in patients with excellent pulmonary reserve. The 5-year survival rates are 60–80% for patients with stage I NSCLC and 40–50% for patients with stage II NSCLC.
Accurate pathologic staging requires adequate segmental, hilar, and mediastinal lymph node sampling. Mediastinal lymph node dissection provides for a significantly larger amount of material, which can refine pathologic (nodal) stage. On the right side, mediastinal stations 2R, 4R, 7, 8R, and 9R should be dissected; on the left side, stations 5, 6, 7, 8L, and 9L should be dissected (Fig. 35-5). Hilar lymph nodes are typically resected and sent with the specimen, although it is helpful to specifically dissect and label level 10 lymph nodes when possible. On the left side, level 2 and sometimes level 4 lymph nodes are generally obscured by the aorta. Although the therapeutic benefit of nodal dissection versus nodal sampling remains controversial, in a recent pooled analysis of three trials, 4-year survival was superior in patients undergoing resection with stages I–IIIA NSCLC who had complete mediastinal lymph node dissection compared with lymph node sampling. Moreover, a complete mediastinal lymphadenectomy adds little morbidity to a pulmonary resection for lung cancer. Thus, the recommendation at this time is that patients should have a complete mediastinal node dissection.
Radiation Therapy in Stages I and II NSCLC There is currently no role for adjuvant radiation therapy in patients following resection of stage I or II NSCLC. Patients with stage I or II disease who refuse or are not candidates for pulmonary resection should be considered for radiation therapy with curative intent. The decision to administer high-dose radiotherapy is based on the extent of disease and the volume of the chest that requires radiation. A systematic review reported 5-year survival rates of 13–39% in patients with stage I or II NSCLC treated with radical radiotherapy. Stereotactic radiation therapy and cryoablation are relatively new techniques that are being used in the treatment of patients with isolated pulmonary nodules who are not candidates for or refuse surgical resection, but their use may be limited by tumor size: ≤5 cm for stereotactic radiotherapy and ≤3 cm for cryoablation therapy.
Chemotherapy in Stages I and II NSCLC A multitude of trials have evaluated the role of adjuvant chemotherapy in patients with resected stage IA–IIIA NSCLC with conflicting results (Table 35-8). A meta-analysis, the Lung Adjuvant Cisplatin Evaluation Study (LACE), reported a 5.4% improvement in 5-year survival for adjuvant chemotherapy compared with surgery alone in patients with stage I–IIIA NSCLC. The effect of cisplatin plus vinorelbine appeared marginally better than other cisplatin-based doublet regimens. The analysis, however, reported a harmful effect for chemotherapy in patients with stage IA disease, with questionable benefit in patients with stage IB disease. Chemotherapy also appeared to be detrimental in patients with poor performance status (ECOG PS2). The results of these studies have led to the recommendation for adjuvant chemotherapy only in patients with stage II or III NSCLC. Chemotherapy should start 6 to 8 weeks after surgery, if the patient has recovered, and should be administered for four cycles. All patients should be treated with a cisplatin-based regimen. Carboplatin is a reasonable consideration in patients who are unlikely to tolerate cisplatin for reasons such as reduced renal function, presence of neuropathy, or hearing impairment.
The treatment of patients with stage IB NSCLC remains controversial. Retrospective subset analyses of randomized phase III trials have reported no benefit for adjuvant chemotherapy in patients with stage IB disease. The only trial to evaluate adjuvant chemotherapy in patients with stage IB NSCLC reported no improvement in overall survival; however, a retrospective analysis of the trial reported a benefit in patients with tumors that were ≥4 cm. At this time, the risks and benefits of chemotherapy should be considered on an individual patient basis.
Four trials have evaluated neoadjuvant chemotherapy (chemotherapy before surgery) in patients with stage I–III NSCLC, of which three reported a trend toward improvement in progression-free and overall survival. However, at this time, no data support the use of neoadjuvant chemotherapy in NSCLC patients.
All patients with resected NSCLC are at high risk of recurrence or developing a second primary lung cancer. Thus, it is reasonable to follow these patients with regular imaging. The most appropriate modality and frequency has not been defined. Given that the majority of patients recur within the first 2 years after therapy, one guideline suggests CT scans of the chest with contrast every 6 months for the first 2 years after surgery, followed by yearly CT scans of the chest without contrast thereafter.
MANAGEMENT OF STAGE III NSCLC The interpretation of the results of clinical trials involving patients with stage III NSCLC has been clouded by a number of issues, including changing diagnostic techniques, different staging systems, and heterogeneous patient populations. In prior studies, patients may have had tumors ranging from nonbulky stage IIIA (clinical N1 nodes with N2 nodes discovered only at the time of surgery, despite a negative mediastinoscopy result) to bulky N2 nodes (lymph nodes >2 cm clearly visible on imaging, or multilevel ipsilateral mediastinal nodes) to clearly inoperable nodes.
Surgery followed by adjuvant chemotherapy is the treatment of choice for patients with stage IIIA disease due to hilar nodal involvement (T3N1). Surgery for N2 disease is more controversial. A randomized phase III trial demonstrated an improvement in progression-free survival but no improvement in overall survival when patients with pathologically staged N2 NSCLC were treated with concurrent chemoradiotherapy (cisplatin and etoposide) and 45 Gy of radiation followed by surgery compared with chemotherapy and 61 Gy of radiotherapy without surgery. Treatment-related mortality is greater in the surgery arm (8% vs 2%), with the majority of deaths occurring in patients undergoing pneumonectomy. In subset analysis, the investigators found survival was improved if a lobectomy was performed but not pneumonectomy compared with chemoradiotherapy alone.
Despite a careful preoperative staging evaluation, as many as a quarter of patients will be found to have metastases to N2 nodes on frozen-section examination at the time of thoracotomy or on final pathologic examination of the surgical specimen. For patients with an occult, single-station mediastinal node metastasis recognized at thoracotomy in which a complete resection of the nodes and primary tumor is technically possible, most thoracic surgeons proceed with the planned lung resection and a mediastinal lymphadenectomy. If a complete resection is not possible or there is multistation or bulky nodal disease or extracapsular nodal disease, then the planned lung resection should be aborted. These patients can then be considered for combined chemoradiotherapy as described later. Although incomplete resection rarely results in long-term survival, collected results indicate that surgery alone in stage IIIA disease (N2 disease) is associated with a 14–30% 5-year survival. The best survival rate is seen in cases with minimal N2 disease and complete resection.
Chemotherapy plus radiation therapy is the treatment of choice for patients with N3 nodal involvement or bulky stage IIIA disease. In general, patients with histologically involved lymph nodes >2 cm in short-axis diameter measured by CT, who have extranodal involvement or multistation disease along with groups of multiple smaller lymph nodes involved, are considered to have bulky, unresectable disease. Randomized phase III trials initially demonstrated an improvement in median and long-term survival for chemotherapy followed by radiation therapy compared with radiation therapy alone. Subsequent trials demonstrated administering concurrent chemotherapy and radiation therapy results in improved survival compared to sequential therapy, albeit with more side effects, such as fatigue, esophagitis, and neutropenia. Therefore, combined modality treatment with chemotherapy and radiation therapy is recommended in patients who are able to tolerate the treatment.
Superior Sulcus or Pancoast Tumors Superior sulcus tumors arise in the apex of the lung and invade adjacent structures producing Pancoast's syndrome: Horner's syndrome, shoulder and/or arm pain, and weakness and atrophy of the muscles of the hand. Patients with these tumors should undergo the same staging procedures as all patients with stage II or III NSCLC. Neoadjuvant chemotherapy or combined chemotherapy and radiation therapy is typically reserved for those patients with N0 or N1 involvement. This approach results in a 33-month median survival and 44% 5-year survival for all patients and a 94-month median survival and 54% 5-year survival in patients with an R0 resection. For patients with Pancoast tumors that have metastatic disease at the time of presentation, radiation therapy with or without chemotherapy may be offered for palliation of symptoms.
TREATMENT OF METASTATIC NSCLC Approximately two-thirds of NSCLC patients present with advanced disease (stage IIIB with a pleural effusion or stage IV) at the time of diagnosis. These patients have a median survival of 4–5 months and a 1-year survival of 10% when managed with best supportive care alone. In addition, a significant number of patients who present with early-stage NSCLC eventually relapse with distant disease. Patients who have recurrent disease have a better prognosis than those presenting with metastatic disease at the time of diagnosis. Standard medical management, the judicious use of pain medications, and the appropriate use of radiotherapy and chemotherapy form the cornerstone of management.
Chemotherapy palliates symptoms, improves the quality of life, and improves survival in patients with stage IV NSCLC, particularly in patients with good performance status. In addition, economic analysis has found chemotherapy to be cost-effective palliation for stage IV NSCLC. However, the use of chemotherapy for NSCLC requires clinical experience and careful judgment to balance potential benefits and toxicities.
First-Line Chemotherapy for Metastatic or Recurrent NSCLC The first indication of the benefit of chemotherapy in patients with advanced NSCLC came from a meta-analysis published in 1995 that reported a survival advantage in patients treated with cisplatin-based chemotherapy compared with those receiving supportive care alone (hazards ratio = 0.73; P < .0001). This led to a multitude of clinical trials comparing different cisplatin-based regimens in patients with advanced NSCLC all reporting a similar magnitude of benefit; 20–30% response rate and an 8- to 10-month median survival (Table 35-9). Chemotherapy was well tolerated in all studies in patients with a good performance status, ECOG PS 0–1.
An ongoing debate in the treatment of patients with NSCLC is the appropriate duration of platinum-based chemotherapy. Several large phase III randomized trials have failed to show a benefit for increasing the duration of platinum-based doublet chemotherapy beyond four to six cycles. In fact, a longer duration of chemotherapy has been associated with increased toxicities and impaired quality of life. Therefore, prolonged therapy (beyond four to six cycles) with platinum-based regimens is not recommended in patients with advanced NSCLC.
Tumor histology has emerged as an important consideration in the treatment of patients with NSCLC. A randomized phase III trial found that patients with nonsquamous NSCLC had an improved survival when treated with cisplatin and pemetrexed compared with cisplatin and gemcitabine, while patients with squamous carcinoma had an improved survival when treated with cisplatin and gemcitabine. This difference in survival is thought to be related to the differential expression of thymidylate synthase, one of the targets of pemetrexed, between tumor types. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), when combined with chemotherapy improves response rate, progression-free survival, and overall survival in patients with advanced disease (see later discussion). However, bevacizumab cannot be given to patients with squamous cell histology NSCLC because of the risk of serious hemorrhagic effects.
Second-Line Chemotherapy and Beyond As first-line chemotherapy regimens improve, a substantial number of patients will maintain a good performance status and a desire for further therapy when they develop recurrent disease. At present, only three drugs are FDA-approved for second-line therapy of NSCLC in the United States, i.e., docetaxel, pemetrexed, and erlotinib. In general, these agents have similar overall response rates of 5–10% (depending on the patient's prior exposure to taxanes and platinum) and yield median survival times of 6–8 months. However, the available drugs have distinct toxicity profiles that can influence their use in the second-line setting. Hematologic toxicity, including febrile neutropenia, is greater for docetaxel than pemetrexed and erlotinib, whereas nonhematologic toxicity, namely rash and diarrhea, is greater with erlotinib. Most of the survival benefit for any of these agents is realized in patients who maintain a good performance status.
AGENTS THAT INHIBIT ANGIOGENESIS Bevacizumab was the first antiangiogenic agent approved for the treatment of patients with advanced NSCLC in the United States. This drug primarily acts by sponging up VEGF and blocking the growth of new blood vessels, which are required for tumor viability. Two randomized phase III trials of chemotherapy with or without bevacizumab had conflicting results. The first trial, conducted in North America, compared carboplatin/paclitaxel with or without bevacizumab in patients with recurrent or advanced nonsquamous NSCLC and reported a significant improvement in response rate, progression-free survival, and overall survival for chemotherapy-plus-bevacizumab–treated patients compared with chemotherapy alone. Toxicities were more frequent in bevacizumab-treated patients. The second trial, conducted in Europe, compared cisplatin/gemcitabine with or without bevacizumab in patients with recurrent or advanced nonsquamous NSCLC and reported a significant improvement in progression-free survival but no improvement in overall survival for bevacizumab-treated patients. Therefore, at this time, carboplatin–paclitaxel and bevacizumab is an approved regimen for first-line treatment of nonsquamous NSCLC in the United States but not in Europe.
AGENTS THAT INHIBIT THE EPIDERMAL GROWTH FACTOR RECEPTOR Erlotinib and gefitinib are oral small-molecule kinase inhibitors that inhibit signaling via EGF-R. These were the first EGF-R inhibitors to be approved for the treatment of patients with NSCLC. A randomized phase III trial compared erlotinib with placebo in previously treated patients with advanced NSCLC and reported an improvement in overall survival for erlotinib compared to placebo. Gefitinib received premarketing approval by the FDA after impressive results seen in phase II trials in patients with previously treated NSCLC; however, a randomized phase III trial found no difference in overall survival between patients treated with gefitinib compared with placebo. These results led to a U.S. FDA-mandated change in the gefitinib indication to include only patients who have previously benefited from this drug. However, gefitinib is still available for the treatment of NSCLC patients in Europe and Asia. Clinical features that have been shown to correlate with responsiveness to EGF-R TKI treatment include female sex, never smoking status, adenocarcinoma histology, and Asian ethnicity. Somatic mutations in the kinase domain of EGF-R and high EGF-R copy number have also been shown to correlate with response and improved survival with oral EGF-R inhibitors.
Two randomized phase III trials conducted in Asia have compared gefitinib with platinum-based chemotherapy in patients with NSCLC. The first trial compared first-line gefitinib with carboplatin–paclitaxel in never or light ex-smokers with newly diagnosed advanced NSCLC. Treatment with gefitinib was associated with a significant improvement in response rate and 12-month progression-free survival. In patients with tumors available for mutation analysis, treatment with gefitinib was favored over chemotherapy in patients with tumors that harbored an EGF-R mutation and chemotherapy was favored in patients with tumors that were EGF-R mutation negative. Quality of life favored treatment with gefitinib. The second trial enrolled only patients with tumors that were EGF-R mutation positive and reported a significant improvement in progression-free survival and disease control for patients treated with gefitinib compared with cisplatin–docetaxel. These and related results suggest standard chemotherapy regimens or gefitinib and erlotinib could be considered for first-line therapy in a subset of advanced NSCLC patients with tumors that harbor the EGF-R mutation.
Cetuximab is an intravenously administered chimeric antibody directed against EGF-R. A randomized phase III trial evaluated treatment with cisplatin–vinorelbine with or without cetuximab in patients with advanced NSCLC and at least one EGF-R–positive cell as determined by immunohistochemistry. The results showed no difference in progression-free survival but a significant improvement in response rate and overall survival in patients treated with cetuximab compared with placebo. A prespecified subgroup analysis showed no improvement in overall survival among patients of Asian ethnicity receiving cetuximab compared with placebo. However, a significant improvement in overall survival was noted among white patients receiving cetuximab; this appeared true regardless of histology. Contrary to patients with colon cancer, KRAS mutation status did not predict response to therapy with cetuximab, although the number of cases examined at the molecular level was suboptimal. Development of acneiform rash was associated with improved overall survival compared with patients with no rash. A second phase III trial in patients with advanced NSCLC with no required EGF-R testing reported no difference in overall survival between patients randomized to carboplatin–paclitaxel or docetaxel with or without cetuximab.
MAINTENANCE THERAPY Maintenance chemotherapy in nonprogressing patients (patients with a complete response, partial response, or stable disease) is a controversial topic in the treatment of NSCLC patients. Two studies have investigated maintenance single-agent chemotherapy with docetaxel or pemetrexed in nonprogressing patients following treatment with first-line platinum-based chemotherapy. Both trials randomized patients to immediate single-agent therapy versus observation and reported improvements in progression-free and overall survival. In both trials, a significant portion of patients in the observation arm did not receive therapy with the agent under investigation upon disease progression; 37% of study patients never received docetaxel in the docetaxel study, and 81% of patients never received pemetrexed in the pemetrexed study. In the trial of maintenance docetaxel versus observation, survival was identical to the treatment group in the subset of patients who received docetaxel on progression, indicating this is an active agent in NSCLC. These data are not available for the pemetrexed study. Currently, maintenance pemetrexed is the only therapy approved by the U.S. FDA following platinum-based chemotherapy in patients with advanced NSCLC. However, maintenance chemotherapy is not without toxicity and at this time should be considered on an individual patient basis.
Two randomized controlled trials have reported improvements in progression-free survival from maintenance treatment with erlotinib compared with placebo in patients with advanced NSCLC following platinum-based chemotherapy.
TREATMENT: Small Cell Lung Cancer
TREATMENT OF LIMITED DISEASE SMALL CELL LUNG CANCER
Surgery SCLC is a highly aggressive disease characterized by its rapid doubling time, high growth fraction, early development of disseminated disease, and dramatic response to first-line chemotherapy and radiation. Surgical resection is not routinely recommended for patients because even those patients with LD-SCLC still have occult micrometastases. If the histologic diagnosis of SCLC is made in patients on review of a resected surgical specimen, such patients should receive standard SCLC chemotherapy as described below. If one employs classic TNM staging categories, two retrospective series have reported high cure rates for adjuvant chemotherapy following resection in patients with stage I or II SCLC.
Chemotherapy Chemotherapy significantly prolongs survival in patients with SCLC. Combination chemotherapy with a platinum agent (cisplatin or carboplatin) and etoposide for four to six cycles is the mainstay of treatment and has not changed in almost three decades. Cyclophosphamide, doxorubicin (Adriamycin), and vincristine (CAV) may be an alternative for patients who are unable to tolerate a platinum-based regimen. Despite response rates to first-line therapy as high as 80%, the median survival ranges from 12 to 20 months for patients with LD and from 7 to 11 months for patients with ED. Regardless of disease extent, the majority of patients relapse and develop chemotherapy-resistant disease. Only 6–12% of patients with LD- and 2% of patients with ED-SCLC live beyond 5 years. The prognosis is especially poor for patients who relapse within the first 3 months of therapy; these patients are said to have platinum-resistant disease. Patients are said to have sensitive disease if they relapse more than 3 months after their initial therapy and are thought to have a somewhat better overall survival. Patients with sensitive disease are thought to have the greatest potential benefit from second-line chemotherapy. Topotecan is the only FDA-approved agent with modest activity as second-line therapy in patients with SCLC.
Radiation Therapy Patients with LD-SCLC are treated with combined modality therapy with cisplatin and etoposide chemotherapy and radiation therapy. A retrospective analysis of patients with SCLC treated with once-daily fractionation found improved local control rates as the total dose delivered was increased from 30 to 50 Gy. Chemotherapy when given concurrently with radiation is more effective than sequential chemoradiation but is associated with significantly more esophagitis and hematologic toxicity. The addition of radiation therapy early on is preferred. Twice-daily (hyperfractionated) radiation has been shown to improve survival in patients with LD-SCLC but is associated with higher rates of grade 3 esophagitis and pulmonary toxicity. It is feasible to deliver once-daily radiation therapy doses up to at least 70 Gy when administered concurrently with cisplatin-based chemotherapy. This higher dose of once-daily radiotherapy may be equivalent or superior to the 45-Gy twice-daily radiotherapy dose. Patients should be carefully selected for concurrent chemoradiation therapy based on good performance status and pulmonary reserve.
Prophylactic Cranial Irradiation Prophylactic cranial irradiation (PCI) should be considered in all patients with LD- and ED-SCLC who have responded to initial therapy. A meta-analysis including 7 trials and 987 patients with LD-SCLC who had achieved a complete remission following primary chemotherapy reported a 5.4% improvement in overall survival for patients treated with PCI. In patients with ED-SCLC who had responded to first-line chemotherapy, PCI reduced the occurrence of symptomatic brain metastases and prolonged disease-free and overall survival compared with no radiation therapy. Long-term toxicities including deficits in cognition have been reported following PCI and are difficult to sort out from the effects of chemotherapy or normal aging.
Molecularly Tailored Lung Cancer Therapy In the past 40 years, clinical research in lung cancer has demonstrated that surgery, systemic chemotherapy, and radiation therapy can all be used to prolong patient survival and/or improve quality of life. However, conventional approaches, especially those that classify patients according to disease histology alone, appear to have reached a therapeutic plateau of effectiveness. One promising future approach to improve the outcome for patients with lung cancer is tailored therapy based on individualized phenotypic or genotypic tumor characteristics. Such a strategy is based on an understanding of the molecular underpinnings of the disease, recognizing that although tumors may appear similar at the histologic level, they do differ from individual to individual. It is hoped that better outcomes can be achieved by matching the most appropriate therapy to a patient at the right time.
For example, one subset of lung cancer can be defined by somatic mutations in EGF-R. EGF-R mutations are almost exclusively found in lung adenocarcinoma and are more common in females, never smokers compared with former or current smokers, and in East Asians compared with Western populations (30–70% vs 8%). These mutations, primarily in-frame deletions in exon 19 and point mutations in exon 21 (L858R), result in constitutive activation of the receptor and are associated with very high response rates (60–90%) to the specific TK inhibitors gefitinib and erlotinib. Almost all patients with these dramatic responses, however, develop acquired resistance. In about half of patients, resistance can be attributed to the emergence of clones harboring a second-site mutation in exon 20 (T790M), which alters binding of drug to the receptor. About 20% of EGF-R mutant tumors from patients with acquired resistance display amplification of a gene encoding a different TK, MET. As a result of these findings, many trials are being conducted in these patients using second-generation EGFR inhibitors that can overcome T790M-mediated resistance or MET inhibitors to target MET-dependent cells.
Another subset of lung adenocarcinoma can be defined by EML4-ALK fusion proteins. These translocations arise from a small inversion within chromosome 2p that leads to the formation of a fusion-gene comprising the N terminal of the echinoderm microtubule–associated protein-like 4 (EML4) gene and the intracellular TK domain of the anaplastic lymphoma kinase (ALK) gene. Patients with lung cancers harboring an ALK fusion protein have demonstrated dramatic responses to small-molecule ALK inhibitors in early clinical trials. The ALK fusion protein is relatively rare, occurring in 3–7% of NSCLCs. Clinical characteristics associated with EML4-ALK–positive lung cancer appears to be a younger age at diagnosis, minimal smoking history, male sex, and adenocarcinoma histology with signet-ring features.
Other biomarkers being explored include molecules that may predict outcomes with conventional chemotherapy. For example, low expression of the DNA repair gene excision repair cross-complementation group 1 (ERCC1) correlates with improved survival after treatment with platinum drugs, whereas tumors that have high expression of ERCC1 are less sensitive to therapy with a platinum agent. In the absence of treatment, lung cancer with low ERCC1 expression has a poorer prognosis.
Ribonucleotide reductase M1 (RRM1) encodes the regulatory subunit of ribonucleotide reductase, the rate-limiting enzyme in DNA synthesis. Ribonucleotide reductase converts ribonucleotide 5-diphosphate to deoxyribonucleotide 5-diphosphate. Notably, gemcitabine, an agent commonly used in the treatment of NSCLC, competes with ribonucleotide 5-diphosphate for incorporation into DNA. Levels of RRM1 expression are significantly and inversely correlated with disease response after two cycles of gemcitabine and carboplatin in patients with locally advanced NSCLC. In addition, low RRM1 mRNA expression levels are associated with a significantly longer median survival compared to high levels.
Thymidylate synthase (TS) catalyzes the methylation of dUMP to dTMP and is the rate-limiting irreversible step in de novo DNA synthesis. TS is one of the targets of the novel folate-based drug pemetrexed, an agent that is FDA-approved as second-line treatment in patients with NSCLC. TS expression is an independent prognostic and predictive factor in several cancers, including lung cancers, and overexpression of TS has been linked to resistance to pemetrexed, an agent commonly employed as second-line treatment in patients with nonsquamous NSCLC. TS mRNA and protein levels are significantly higher in squamous cell carcinomas and small cell carcinomas of the lung as compared with adenocarcinomas. A randomized phase III trial reported that cisplatin plus gemcitabine was more effective in squamous cell carcinomas; cisplatin plus pemetrexed was found to be more effective in adenocarcinomas and large cell carcinomas. Molecular markers are likely to play an increasing role in helping guide treatment decisions.