Best Practices in lung cancer – November 2017 Vol 8

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Lung Cancer

Lung Cancer. Now What? Plans and How We “Navigate” Them

Amy M. Norton, RN, MSN, ONN-CG(T)1; Dawn M. Deacon, RN, BSN, OCN, ONN-CG1; Wendy L. Brooks, RN, ONN-CG(T)1; Erin L. Terwilliger, RN, BSN, ONN-CG2
1Sarah Cannon Cancer Institute – HCA Midwest Division; 2AstraZeneca Pharmaceuticals LP 

Ali Mokdad, PhD, reported in JAMA that “cancer mortality rates in the United States dropped from 240.2 to 192.0 per 100,000 population between 1980 and 2014.”1 However, according to the National Comprehensive Cancer Network (NCCN), “Only 17.7% of all patients with lung cancer are alive 5 years after diagnosis,”2 and there will be an estimated 222,500 new cases of lung and bronchial cancers diagnosed in 2017,2 resulting in an estimated 155,870 deaths.2 We are fortunate that we are beginning to see patients with better outcomes become more common.

Screenings, lung nodule programs, breakthroughs in identification of genetic mutations, better and less invasive diagnostics, more precise radiation equipment, new medications, as well as new innovative therapies are on the rise. These advances are improving patients’ quality of life and outcomes. To be effective, navigators are required to stay up to date on the constantly changing landscape of lung cancer care.

Surgery

Surgery remains the gold standard of treatment for lung cancer patients diagnosed with early-stage disease. Other treatment options are available for patients who are not eligible for surgery due to performance status, comorbidities, advanced stage, or personal preference. Advanced radiation techniques may be utilized for patients who are considered to be at too high a risk for complications from either surgery or anesthesia.3 If patients are determined to be surgical candidates, there are multiple surgical approaches to consider. The first 2 methods we will discuss are “minimally invasive” approaches.

Video-assisted thoracic surgery (VATS) is an approach used in select patients who meet specific surgical criteria. The “benefits of VATS in lung surgery includes smaller incisions, less blood loss, less pain, less complications, less respiratory compromise, faster recovery times, and shorter lengths of stay.”4 “Demonstrated safety, decreased morbidity, and equivalent efficacy of this minimally invasive technique have led to the acceptance of VATS as a standard surgical modality for early-stage lung cancer and increasing application in more advanced disease.”5 For all its positive aspects, the VATS procedure has been noted to have its drawbacks for surgeons. VATS has documented issues with “counter-intuitive hand movements to manipulate the instruments, an instrument fulcrum effect, and tremor amplification. The surgeon stands over the patient to operate the instruments, while the virtual operating field is displayed on a monitor some distance away, disrupting eye-hand coordination.”6

Robotic thoracic surgery (RTS) has emerged as an alternative to VATS for perceived advantages with the same results.4 Whereas most VATS endoscopes provide 2-D images with limited magnification, RTS has 3-D imaging, and the robotic technology allows more natural hand and wrist movement utilizing computer-assisted robotic arms. This translates to more precise movements inside the patient. The surgeon works at a console away from the bedside and is able to view the operating fields on the monitor.6 The cost of the robotic systems remains prohibitive, however, and thus is not an option for every facility.6

Open surgical procedures are still performed in multiple circumstances for lung cancer patients. The risks of adverse events and side effects remain higher than with minimally invasive procedures. Pain can be more difficult to manage with open procedures and can result in respiratory failure due to splinting, pneumonia due to ineffective coughing and secretion clearance, and post-thoracotomy pain syndrome, which can be chronic.7 The reason we see so much more pain is that a “thoracotomy requires a very painful incision involving multiple muscle layers, rib resection, and continuous motion as the patient breathes.”7

Regardless of the surgical approach chosen, if surgery is being performed with curative intent, the gold standard requires that a cervical mediastinoscopy be performed as a means of mediastinal biopsy prior to surgical resection.8

Historically, wedge resections have typically been reserved for patients with limited cardiopulmonary function who could not tolerate losing an entire lobe. A wedge resection is, as the name implies, a procedure in which a wedge portion of the lobe containing tumor is resected, or “wedged” out, and remaining margins assessed for tumor cells. It can be performed by open or minimally invasive approaches and has fewer side effects than a lobectomy because the patient only loses a portion of that lobe. The progression-free success rate is low enough that it is not utilized often, and definitely not without comprehensive presurgical staging.9

Segmentectomy, like wedges, are only performed on N0 patients after comprehensive staging. They require excision of at least 1 bronchopulmonary segment with ligation and division of the bronchi and vessels serving the affected segments. They tend to also be performed on patients with health issues that would prevent lobectomy.6

Lobectomy remains the standard of care for stage I/II non–small cell lung cancer (NSCLC), along with lymph node dissection. This can be done by utilizing any of the approaches listed above, and side effects vary based on approach, as previously discussed. Patients must demonstrate adequate pulmonary function prior to lobectomy to be eligible.6

Pneumonectomy is a complete removal of 1 entire lung. This procedure is utilized when tumors involve multiple lobes of the lung, the hilum, lymph nodes, or the proximal bronchus. Pneumonectomy can be “simple,” meaning that it involves removal of the lung with stapling of the bronchus; or “radical,” meaning that the mediastinal lymph nodes are also removed.10

A sleeve lobectomy procedure is considered and practiced as the standard therapy for central lung cancers that are anatomically suitable and is noted to have a long-term advantage over pneumonectomy. Initially, sleeve lobectomy was considered as a pneumonectomy alternative for patients with low-grade, centrally located lesions such as those that involve the main or lobar bronchi. Over time, sleeve lobectomy has become a first-line intervention, regardless of grade.11

Chemotherapy

Navigator numbers are increasing rapidly nationwide. Many navigators coming into the role of oncology navigation possess little or no oncology background. These navigators may be new to the field or may not be nurses. With this in mind, we should discuss chemotherapy. What exactly is chemotherapy? Most know that chemotherapy is given to patients with a diagnosis of cancer, but what exactly is it, and how does it work? The Merriam-Webster dictionary defines chemotherapy as “the therapeutic use of chemical agents to treat disease; especially: the administration of one or more cytotoxic drugs to destroy or inhibit the growth and division of malignant cells in the treatment of cancer.”12

What does this mean? We have broken our explanation down even further. There are 5 main classifications of chemotherapy, and each has its own role in the care of cancer patients. However, only some classifications and some drugs within these classifications are currently used for lung cancer. They are as follows13:

1. Alkylating agents: These agents are most active in the resting phase of the cell. These types of drugs are cell-cycle nonspecific. There are several types of alkylating agents used in chemotherapy treatments13:

  • Mustard gas derivatives: cyclophosphamide
  • Metal salts: carboplatin, cisplatin, and oxaliplatin.

2. Plant alkaloids: Chemotherapy treatments derived from certain types of plants. The vinca alkaloids are made from the periwinkle plant (catharanthus rosea). The taxanes are made from the bark of the Pacific yew tree (taxus). The vinca alkaloids and taxanes are also known as antimicrotubule agents. The podophyllotoxins are derived from the mayapple plant. Camptothecan analogs are derived from the Asian “Happy Tree” (Camptotheca acuminata). Podophyllotoxins and camptothecan analogs are also known as topoisomerase inhibitors, which are used in certain types of chemotherapy. The plant alkaloids are cell-cycle specific. This means they attack the cells during various phases of division13:

  • Vinca alkaloids: vinblastine and vinorelbine
  • Taxanes: paclitaxel and docetaxel
  • Podophyllotoxins: etoposide
  • Camptothecan analogs: irinotecan and topotecan

3. Antitumor antibiotics: Chemotherapy treatments made from natural products produced by species of the soil fungus Streptomyces. These drugs act during multiple phases of the cell cycle and are considered cell-cycle specific. There are several types of antitumor antibiotics; however, we will not discuss them further because they are not utilized in the treatment of lung cancer.13

4. Antimetabolites: Types of chemotherapy treatments that are very similar to normal substances within the cell. When the cells incorporate these substances into the cellular metabolism, they are unable to divide. Antimetabolites are cell-cycle specific. They attack cells at very specific phases in the cycle. Antimetabolites are classified according to the substances with which they interfere13:

  • Folic acid antagonist: methotrexate
  • Pyrimidine antagonists: capecitabine and gemcitabine

5. Topoisomerase inhibitors: Types of chemotherapy drugs that interfere with the action of topoisomerase enzymes (topoisomerase I and II). During the process of chemotherapy treatments, topoisomerase enzymes control the manipulation of the structure of DNA necessary for replication13:

  • Topoisomerase I inhibitors: irinotecan, topotecan
  • Topoisomerase II inhibitors: etoposide

Per NCCN guidelines, oncologists determine the best therapies based on the type and stage of the cancer. Lung cancer has 2 main histologies: small cell lung cancer (SCLC) and NSCLC. In limited-stage (stage I) SCLC, a patient may be determined to be eligible for surgical resection followed by postoperative systemic treatment. Patients with limited-stage (stage II/III) SCLC with proven nodal involvement benefit from surgical interventions and should be treated with postoperative systemic therapy along with concurrent mediastinal radiation therapy. Platinum doublet therapy is used in extensive-stage (stage IV) SCLC.14

Chemotherapy is often given in conjunction with preventive medications to control side effects from either the chemotherapy or the disease, including antiemetics, intravenous fluids, vitamin B12 injections, zoledronic acid, and denosumab.15 Zoledronic acid and denosumab are medications that can be used to treat cancer-induced hypercalcemia and help to prevent fractures from bone metastases. Symptoms and conditions to watch for with zoledronic acid and denosumab are “ostalgia, nausea, fever (usually mild and short-lived), fatigue, anemia, vomiting, and constipation.”15 One additional severe side effect can be osteonecrosis (bone loss in the jaw).16 The symptoms of this disorder are jaw pain, numbness, loose teeth, infection, and swelling or abnormal healing after dental procedures. Unfortunately, having cancer, or having been treated with chemotherapy or radiation, increases your risk of this severe side effect.16

Side effects and chemotherapy are inseparable in patients’ minds and are often the first question asked after hearing “chemotherapy.” The good news is that we can more effectively control side effects now than we could many years ago. Side effects may include fatigue, pain, mouth and throat sores, diarrhea, nausea and vomiting, constipation, and blood disorders. The normal cells most likely to be damaged by chemotherapy are17:

  • Forming cells in the bone marrow
  • Hair follicles
  • Cells in the mouth, digestive tract, and reproductive system

Some chemotherapy drugs can damage cells in the heart, kidneys, bladder, lungs, and nervous system.17

Radiation

Radiation therapy is the use of high-energy x-rays to treat diseases such as cancer; it is delivered in doses called fractions. According to research, 3 of 4 patients with cancer are likely to receive radiation therapy in some form.18 Radiation therapy damages the DNA of replicating cells and effectively stops the cell cycle, thus killing cancer cells.19 Definitive radiation therapy is utilized for patients with curative intent, and palliative radiation is utilized for symptom management. Although some radiation can be done internally, radiation for lung cancer is delivered externally and is noninvasive.

External beam therapy is the most common radiation delivery method and is most commonly delivered via a medical linear accelerator.18,20 There are 3 external beam techniques20:

1. 3-D conformal radiation therapy (3-D CRT) combines multiple radiation fields to deliver precise doses of radiation

2. Intensity-modulated radiation therapy, a specialized form of 3-D CRT in which the intensity of the radiation beams is varied

3. Stereotactic radiation therapy, or radiosurgery, is a specialized form of radiation given precisely in high doses to a defined target over a shortened course of treatment

  • Stereotactic radiosurgery (SRS) is often used as a treatment for brain and spine metastases. Gamma Knife is a common device utilized for SRS
  • Stereotactic body radiation therapy (SBRT) is used to treat tumors outside the brain and spine. CyberKnife is a common device used to deliver SBRT treatments

NCCN guidelines recommend SBRT in both stage I and II NSCLC patients with node-negative disease who are determined to be medically inoperable. In stage I patients, SBRT “confers a local control rate of 80%-90%, potentially equivalent to surgery.”21 Stage II patients with N1 disease should pursue definitive chemoradiation. Radiation therapy plays a definitive role in stage III NSCLC patients. NCCN recommendations vary in these patients based on both tumor size and node status; it is recommended the guidelines be reviewed on a patient-by-patient basis.21

SCLC and NSCLC are treated differently per NCCN guidelines. Combination chemoradiation is recommended for limited-stage SCLC (M0), except in the presence of T1-2 node-negative stage I disease. Diagnosis at this early stage remains uncommon. The role of radiation varies in extensive-stage disease depending on the site of metastases and patient symptoms. Radiation is not indicated if patient is asymptomatic and without brain metastases. Whole brain radiation is indicated in the treatment of brain metastases before systemic treatment if patient is symptomatic, and after systemic treatment if patient is asymptomatic. There are also multiple sites/conditions that may be given radiation for palliation such as superior vena cava syndrome, lobar obstruction, and bone metastases. Although it is known that extensive-stage patients cannot be cured, there is a proven benefit from consolidative thoracic radiation if they respond well to therapy, such as fewer symptomatic chest recurrences and improved long-term survival in some patients.14

Prophylactic cranial irradiation (PCI) reduces incidences of brain metastases and prolongs disease-free and overall survival. PCI is indicated for patients with both limited- and extensive-stage SCLC as long as they have at least a partial response to treatment per NCCN recommendations. Recommendations exclude patients with poor performance status or impaired neurocognitive functioning.22

As with all treatments, radiation is not without side effects. The most notable side effect of radiation, as with most cancer treatments, is fatigue.23 The level of fatigue is variable by patient, but recommended treatment for radiation-related fatigue includes exercise and physical activity.24 In a study of cancer patients, “those who met physical activity guidelines reported less fatigue.”23 There are many other possible side effects with radiation, but they vary from patient to patient and can be affected by the exact location being treated as well as the technique being utilized. These can include pneumonitis in about 5% to 15% of patients receiving radiation to the chest, fibrosis, esophageal injuries, decreased cognitive function, and/or memory loss.25

Radiation is delivered in doses called fractions. Treatments occur daily, usually Monday through Friday, over the course of several weeks depending on the site of treatment and intent of therapy. The 4 R’s of radiation therapy detail the need for repeated doses over time to achieve the desired effect of therapy26:

  • Repair: Normal cells are better at repairing themselves after radiation damage and may start doing so as soon as 3 hours posttreatment
  • Repopulation: This allows normal cells to grow and divide, enabling them to continue carrying out their normal functions
  • Reoxygenation: Is required for effective treatment. “Oxygen has been known as one of the most potent modifiers of radiation sensitivity, and hypoxic cells have been repeatedly shown to be 2 to 3 times more resistant to radiation”26
  • Redistribution: Refers to the redistribution of cells throughout the cell cycle. Cells in mitosis are most sensitive to radiation, and those in the S phase are most resistant. Fractionation allows redistribution of radioresistant S-phase cells to a more sensitive phase of the cell cycle

Targeted Therapies and Immunotherapies

Targeted therapies and immunotherapies are changing the way metastatic lung cancer is treated. Ettinger et al state “several biomarkers have emerged as predictive and prognostic markers for NSCLC.”2 A predictive biomarker is utilized to assess how a patient will respond to a therapy, whereas a prognostic biomarker shows patient survival regardless of treatment received by allowing us to assess the tumor’s level of aggressive behavior.2 Some of the predictive biomarkers are anaplastic lymphoma kinase (ALK), C-Ros oncogene 1 (ROS1), and epidermal growth factor receptor (EGFR). Emerging biomarkers include human epidermal growth factor receptor 2/erythroblastic leukemia viral oncogene homolog 2 (HER2/ERBB2), BRAF V600E proto- oncogene (BRAF), RET proto-oncogene (RET) and c-MET oncogene (MET).2

Tyrosine kinase inhibitors (TKIs) are medications that interrupt cellular growth signals by binding to specific receptors on cells. This has the effect of potentially slowing growth, stopping growth, or even causing cancer cell death.27 Some TKIs for EGFR include erlotinib, gefitinib, and afatinib. Osimertinib is available to treat an EGFR T790M mutation after patients progress on their first-line TKI. Patients with ALK, ROS1, and MET mutations may be treated with crizotinib. Ceritinib targets ALK and IGF-1 receptors, and alectinib targets ALK and RET.

TKIs are oral medications and tend to have fewer side effects than standard chemotherapy treatments.2

Side effects are generally quite mild but can include the following:27,28

  • Decreased white blood cell count, increasing infection risk
  • Decreased platelet counts, increasing risk of bleeding or clotting disorders
  • Fatigue
  • Nausea, vomiting, or anorexia
  • Diarrhea
  • Heartburn
  • Headache
  • Muscle cramps
  • Fluid retention and swelling, particularly ocular swelling
  • Rash, which can appear as early as 2 weeks into treatment
  • Liver problems/failure
  • Pulmonary arterial hypertension in rare cases
  • Sores of the mucous membranes (nose, mouth, etc)
  • Nail infections
  • Eye, vision problems
  • Kidney problems

Diarrhea and rash are the most common side effects seen with TKIs in lung cancer patients.27 Diarrhea should be discussed in detail with patients prior to the initiation of treatment. Although typically mild to moderate in nature, it is essential to ensure that the patient reports occurrences early to prevent more severe complications. Rash occurs in more than 50% of patients taking EGFR inhibitors and has been shown to “be an indication of treatment efficacy.”29

Research has shown that “patients who did not develop a skin rash had a survival so short that it is very unlikely that erlotinib caused any meaningful survival increase.”30 Navigators should reinforce skin care for patients taking TKIs, including the following:29

  • Keep dry skin moisturized using alcohol-free products
  • Limit time in the sun, in addition to utilizing broad-spectrum sunscreens
  • Limit use of any products containing soap, alcohol, perfume, or acne products unless prescribed by a physician
  • Limit skin drying by shortening showers and using warm water versus hot water

Immunotherapies have become valuable tools in treatment of both NSCLC and SCLC. They can be utilized as first-line therapy in certain cases, as well as for patients who have had disease progression on other therapies. The aim of immunotherapy is to enhance the immune response specifically directed to the tumor by “removing the brakes” on T-cell–mediated responses by blocking the PD-1 pathway, allowing the patient’s own immune system to fight the cancer.31 They are sometimes quite effective at this and can potentially quadruple 5-year survival percentages in advanced NSCLC.32 Cytotoxic T cells may have a PD-1 receptor or PD-1 ligand (PD-L1) that increases antitumor immunity. Testing for PD-L1 is not always required prior to prescribing immunotherapy, yet it is quickly becoming a standard of care. PD-L1 correlates to the patient’s likelihood to respond.2 Nivolumab, pembrolizumab, atezolizumab, and ipilimumab are all FDA-approved immunotherapies utilized in lung cancer in the United States.31

Side effects include:28

  • Fatigue
  • Difficulty breathing, cough, lung inflammation
  • Muscle, bone, and joint pain
  • Anorexia
  • Nausea
  • Constipation
  • Hormonal imbalances (ie, thyroid disorders)

Conclusion

Although we can never claim to encompass every aspect of every treatment plan a lung cancer patient might encounter in this one article, it is our hope that this has provided a comprehensive overview, and perhaps even a learning opportunity. The “face” of lung cancer is ever changing, from staging to treatment protocols. With each new discovery, a little more hope is given to our patients. To all our fellow navigators, fight on!

References

  1. Mokdad AH, Dwyer-Lindgren L, Fitzmaurice C, et al. Trends and patterns of disparities in cancer mortality among US counties, 1980-2014. JAMA. 2017;317:388-406.
  2. Ettinger DS, Wood DE, Aisner DL, et al. Non-small cell lung cancer, Version 5.2017, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2017;15:504-528.
  3. Helwick C. Stage I lung cancer: treatment advances have changed the game. The ASCO Post. 2017;8(7):84-86.
  4. Ye X, Xie L, Chen G, et al. Robotic thoracic surgery versus video-assisted thoracic surgery for lung cancer: a meta-analysis. Interact Cardiovasc Thorac Surg. 2015;21:409-414.
  5. Dziedzic D, Orlowski T. The role of VATS in lung cancer surgery: current status and prospects for development. Minim Invasive Surg. 2015;2015:938430.
  6. Veronesi G. Robotic lobectomy and segmentectomy for lung cancer: results and operating technique. J Thorac Dis. 2015;7(suppl 2):S122-S130.
  7. Gerner P. Postthoracotomy pain management problems. Anesthesiol Clin. 2008;26:355-367.
  8. Falase B, Ogadinma M, Majekodunmi A, et al. The role of cervical mediastinoscopy in Nigerian thoracic surgical practice. Pan Afr Med J. 2016;24:135.
  9. Shennib H, Bogart J, Herndon J, et al. Video-assisted wedge resection and local radiotherapy for peripheral lung cancer in high-risk patients: the Cancer and Leukemia Group B (CALGB) 9335, a phase II, multi-institutional cooperative group study. J Thorac Cardiovasc Surg. 2005;129:813-818.
  10. Adams LA, Berg CD, Camporeale JM, et al. Non-small cell lung cancer. In: Houlihan NG, Tyson LB, eds. Lung Cancer. 2nd ed. Pittsburgh, PA: Oncology Nursing Society; 2012:105-106.
  11. Han Y, Zhou S, Yu D, et al. Video-assisted thoracic surgery (VATS) left upper sleeve lobectomy with partial pulmonary artery resection. J Thorac Dis. 2013;5(suppl 3):S301-S303.
  12. Merriam-Webster. Chemotherapy. www.merriam-webster.com/dictionary/chemotherapy. Accessed August 22, 2017.
  13. Chemocare. Types of Chemotherapy. http://chemocare.com/chemotherapy/what-is-chemotherapy/types-of-chemotherapy.aspx. Accessed August 22, 2017.
  14. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Non-Small Cell Lung Cancer. Version 9.2017. www.nccn.org. Accessed October 4, 2017.
  15. Chemocare. Zometa. http://chemocare.com/chemotherapy/drug-info/Zometa.aspx. Accessed September 9, 2017.
  16. Drugs.com. Xgeva. www.drugs.com/xgeva.html. Accessed September 7, 2017.
  17. American Cancer Society. Chemotherapy Side Effects. www.cancer.org/treatment/treatments-and-side-effects/treatment-types/chemotherapy/chemotherapy-side-effects.html. Accessed September 7, 2017.
  18. Camporeale J. Basics of radiation treatment. Clin J Oncol Nurs. 2008;12:193-195.
  19. Smith Y. Radiation Therapy and Cancer. News Medical. www.news-medical.net/health/Radiation-Therapy-and-Cancer.aspx. Updated May 4, 2015. Accessed September 9, 2017.
  20. Schreiber GJ. General Principles of Radiation Therapy. http://emedicine.medscape.com/article/846797-overview. Updated October 15, 2015. Accessed September 10, 2017.
  21. Helwick C. Stereotactic Body Radiation Therapy an Effective Option for Early-Stage Lung Cancer Patients. The ASCO Post. www.ascopost.com/issues/september-1-2014/stereotactic-body-radiation-therapy-an-effective-option-for-early-stage-lung-cancer-patients.aspx. 2014. Accessed September 10, 2017.
  22. Zhang W, Jiang W, Luan L, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer: a systematic review of the literature with meta-analysis. BMC Cancer. 2014;14:793.
  23. Vijayvergia N, Shah PC, Denlinger CS. Survivorship in non-small cell lung cancer: challenges faced and steps forward. J Natl Compr Canc Netw. 2015;13:1151-1161.
  24. Mitchell SA, Hoffman AJ, Clark JC, et al. Putting evidence into practice: an update of evidence-based interventions for cancer-related fatigue during and following treatment. Clin J Oncol Nurs. 2014;18(suppl):38-58.
  25. Bruner DW, Haas ML, Gosselin-Acomb TK. Manual for Radiation Oncology Nursing Practice and Education. 3rd ed. Pittsburgh, PA: Oncology Nursing Society; 2006.
  26. Pajonk F, Vlashi E, McBride WH. Radiation resistance of cancer stem cells: the 4 R’s of radiobiology revisited. Stem Cells. 2010;28:639-648.
  27. University of Michigan. Tyrosine Kinase Inhibitors (TKIs). www.uofmhealth.org/health-library/tv7950. Updated November 8, 2011. Accessed September 30, 2017.
  28. Hanisch LJ, Marlow L. NCCN Guidelines for Patients. Non-Small Cell Lung Cancer. 1st ed. Fort Washington, PA: National Comprehensive Cancer Network; 2015.
  29. Hirsh V. Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer. Curr Oncol. 2011;18:126-138.
  30. Johnson JR, Cohen M, Sridhara R, et al. Approval summary for erlotinib for treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Clin Cancer Res. 2005;11:6414-6421.
  31. Yang L, Wang L, Zhang Y. Immunotherapy for lung cancer: advances and prospects. Am J Clin Exp Immunol. 2016;5:1-20.
  32. Goodman A. Five-year survival quadrupled in responders to immunotherapy for non-small cell lung cancer. The ASCO Post. 2017;8(8):4-5.

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