Hospital Medicine

Non-small cell lung cancer

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Non-Small Cell Lung Cancer

I. What every physician needs to know.

Lung cancer is the leading cause of cancer death in the United States. Fewer than 18% of lung cancer patients are alive 5 years or more after diagnosis. Non-small-cell lung cancer (NSCLC) is an epithelial malignancy of the lung/bronchus. It is distinct and separate from small-cell lung cancer based on its histological features, clinical and biologic behavior, and management. About 85% of lung cancers are non-small-cell carcinomas. The classification of NSCLC can be broadly subdivided into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinoma is the histologic subtype most commonly linked to women and to light smokers or never-smokers.

II. Diagnostic Confirmation: Are you sure your patient has Non-Small Cell Lung Cancer?

A. History Part I: Pattern Recognition:

About 5% of patients who have a new diagnosis of lung cancer are asymptomatic. The majority of lung cancer patients who have symptoms at the time of initial presentation are diagnosed with local regional or advanced disease. Key symptoms and/or signs include cough, chest pain, hemoptysis, dyspnea, weight loss, bone pain, fatigue, dysphagia, wheezing/stridor, hoarseness, shoulder or arm pain, or Horner's syndrome. Patients can also present with a thromboembolic event or paraneoplastic syndrome such as hypercalcemia or hypertropic pulmonary osteoarthropathy.

B. History Part 2: Prevalence:

Approximately 85-90% of cases of lung cancer are related to tobacco smoke. Active tobacco use is the leading risk factor. Results from the National Lung Screening Trial showed that screening individuals with high risk factors using low-dose chest CT decreased the lung cancer mortality rate by 20%. High risk individuals were determined to be current or former smokers who quit within 15 years who are 55 to 74 years of age with 30 or more pack-year smoking history.

Radon exposure is the prevailing cause of lung cancer in never-smokers, followed by second hand smoke exposure. Asbestos and tobacco smoke act synergistically to increase the risk of lung cancer.

Agents such as polycyclic aromatic hydrocarbons, chloromethyl ethers, silica, chromium, nickel, arsenic, and ionizing radiation are linked to lung cancer. Dietary supplemention with beta-carotene has been suggested to increase the risk for lung cancer. Genetic contribution to risk of developing lung cancer is less well understood. 3p deletions are seen in a majority of non-small-cell lung carcinomas and have been detected early in the disease process.

C. History Part 3: Competing diagnoses that can mimic Non-Small Cell Lung Cancer.

Metastatic carcinoma to the lung

Small cell lung cancer

Malignant mesothelioma

Lymphoma

Sarcoma

Pulmonary infection (acute bronchitis, lung abscess, tuberculosis, aspergilloma, pneumonia)

Sarcoidosis

Asbestosis

D. Physical Examination Findings.

Weight loss

Dyspnea

Wheeze (often unilateral)

Diminished breath sounds or rales or rhonchi

Dullness to percussion of the lungs

Palpable supraclavicular or axillary lymphadenopathy

Hepatomegaly

Abdominal distension

Clubbing

Altered mental status

Motor or sensory neurologic deficits

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

CBC, platelet count, serum electrolytes, BUN, serum creatinine, calcium, albumin, total bilirubin, liver transaminases, and serum alkaline phosphatase.

Pulmonary function tests, if surgical exploration or resection, or stereotactic ablative body radiotherapy is considered.

Sputum cytology is considered to be an insensitive tool for the diagnosis of NSCLC.

The diagnosis of NSCLC is established by tissue biopsy or cytology examination of bronchial brushing or washing specimen(s), or pleural fluid. Tissue can be obtained by endobronchial biopsy, transbronchial biopsy, percutaneous needle biopsy (core needle biopsy is preferred to fine needle aspirate), video-assisted thorascopic surgery, open thoracotomy, mediastinoscopy or mediastinotomy.

A diagnostic thoracentesis or thoracotomy is recommended if a pleural effusion is present. The pleural fluid obtained should be sent for cytology analysis. Immunohistochemical staining is used to distinguish primary lung adenocarcinoma from adenocarcinoma metastatic to the lung and from malignant pleural mesothelioma. Most primary lung adenocarcinomas are TTF-1 and CK-7 positive and CK-20 negative. Calretinin and WT-1 are specific immunostains for malignant mesothelioma.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Chest X-Ray (optional)

Computed tomography (CT) chest/thorax, and upper abdomen with contrast, including liver and adrenals, done with contrast enhancement.

PET/CT scan

Brain magnetic resonance imaging [MRI] (except for stage IA; optional for stage IB)

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

III. Default Management.

Treatment of NSCLC is according to stage of disease. For local disease (stages I and II), complete surgical resection is the treatment of choice. Lobectomy is preferred over pneumonectomy. Sublobar resection is appropriate in select patients. Re-resection of positive surgical margins is preferred to adjunct radiation therapy. For patients with medically inoperable, node negative stage I disease, initial treatment with stereotactic ablative body radiotherapy results in higher local control than conventional radiation therapy. Definitive treatment with conventional radiation therapy is otherwise used for medically inoperable stage I and II disease. Adjuvant cisplatin-based doublet systemic chemotherapy is recommended for patients with completely resected stage II disease.

A superior sulcus (Pancoast tumor) is treated with preoperative concurrent chemoradiaton, followed by surgery and adjuvant cisplatin-based doublet systemic chemotherapy. Unresectable superior sulcus tumor is treated with definitive concurrent chemoradiation.

The choice of initial treatment in patients with locally advanced NSCLC is less well-defined and is determined by the extent of lymph node involvement.

For patients with recurrent and metastatic NSCLC, the histologic subtype should be determined prior to initiation of systemic chemotherapy so the best treatment option can be selected. Tumor analysis for EGFR mutation and ALK gene rearrangement is recommended for patients with adenocarcinoma, large cell carcinoma, or NSCLC, not otherwise specified. Treatment with platinum-based combination systemic chemotherapy is superior to best supportive care alone in patients who have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. New targeted agents are FDA-approved for use in the first, second, and third-line treatment of patients with metastatic NSCLC.

A. Immediate management.

Patients with a new diagnosis of NSCLC can initially present with spinal cord compression, superior vena cava syndrome, symptomatic brain metastases, hypercalcemia, hemoptysis, endobronchial obstruction, large pleural effusion, or pneumonia.

A delay in evaluation and treatment of spinal cord compression (SCC) can result in permanent bowel/bladder dysfunction or paralysis. Approximately 70% of SCC occurs in the thoracic region. Symptoms progress from dull, aching constant and worsening back pain to paresthesia of extremities, then motor weakness, ataxia, and autonomic dysfunction. A clinical suspicion of spinal cord compression should trigger quick initiation of therapy with dexamethasone, even prior to radiographic diagnosis. MRI of the entire spine with and without contrast is the preferred imaging study to diagnose spinal cord compression. Neurosurgery and radiation oncology consultation(s) are urgently required.

Superior vena cava syndrome can result in life-threatening increased intracranial pressure or airway compromise. Clinical signs/symptoms may develop suddenly. These include prominence of neck or chest wall vasculature, facial plethora and facial and periorbital edema, cyanosis, alteration of mental status, swelling of upper extremities, dyspnea, chest pain, hoarseness, wheezing, stridor, cough, or sensation of "fullness" in the head. Emergency treatment with radiation therapy is required in the setting of respiratory compromise or development of neurologic symptoms.

Patients with symptomatic brain metastases require prompt initiation of dexamethasone. In asymptomatic patients with little or no tumor-associated edema or mass effect, dexamethasone can be reserved until first indication of neurologic signs or symptoms. Neurosurgery and radiation oncology consultation(s) are essential. The American Academy of Neurology recommends against use of prophylactic anticonvulsants in newly diagnosed brain tumor patients who have not experienced a seizure.

Patients with corrected serum calcium levels higher than 12 mg/dl or symptoms of hypercalcemia should be treated for correction of the hypercalcemia.

Massive hemoptysis, although uncommon, can be immediately fatal. The airway must be secured as the first step in management. Bronchoscopy can be performed for diagnosis and therapeutic purpose. Emergent thoracotomy with resection of the involved lung may be necessary in rare cases. Thoracic radiation is the preferred management option for moderate hemoptysis. Endobronchial brachytherapy is an alternative approach for patients who have had prior treatment with external-beam radiation.

Patients who present with endobronchial obstruction require urgent evaluation by the pulmonary service for consideration of therapeutic bronchoscopy and airway stent placement.

Initial management of a large pleural effusion requires diagnostic and therapeutic thoracentesis or chest tube drainage. Pleurodesis or placement of a chronic indwelling pleural catheter may become necessary.

B. Physical Examination Tips to Guide Management.

Monitor for alteration of mental status, hemodynamic instability, tachypnea, fever, weight loss, pallor, distention of neck veins, presence of rales, rhonchi, or wheezes or dullness to percussion on lung examination, new heart murmur or development of a friction rub, peripheral edema, presence of jaundice, ascites, hepatomegaly or splenomegaly, development of peripheral sensory loss or focal motor weakness, ataxia, loss of coordination or gait disturbance, skin or nail changes, or bone/vertebrae tenderness.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Before initiation of chemotherapy and prior to administration of each cycle, the results of a complete blood count with differential cell count and a complete metabolic profile are reviewed by the patient's oncologist. Dose modification is made by the oncologist as appropriate. Tumor response to chemotherapy will be assessed by radiographic imaging studies, usually after the initial first or second cycle, then every 2 – 4 cycles.

There is no tumor marker specific for NSCLC.

D. Long-term management.

For patients with stage I - IV who have no clinical or radiographic evidence of disease after initial treatment, the National Comprehensive Cancer Network Guidelines Version 2.2016 for Non-Small Cell Lung Cancer recommend surveillance. This consists of a history and physical examination and chest CT with or without contrast every 6 - 12 months for 2 years, then history and physical examination and low-dose non-contrast enhanced chest CT annually. Additionally, smoking cessation advice, counseling and pharmacotherapy are recommended. FDG PET/CT or brain MRI is not indicated for routine follow-up.

Patients should receive annual influenza vaccination, pneumococcal vaccination with revaccination as appropriate and herpes zoster vaccine are recommended. The physician should provide counseling regarding maintenance of a healthy weight, regular physical activity, healthy diet with emphasis on plant sources, and limited consumption of alcohol if one consumes alcoholic beverages. Patients should have routine blood pressure, cholesterol, and glucose monitoring, bone density testing as appropriate, routine dental examinations, and routine sun protection.

Long-term complications of treatment can include premature menopause, infertility, sterility, radiation pneumonitis and/or pulmonary fibrosis and/or esophageal stricture, development of a secondary malignancy or secondary leukemia, neurocognitive deficit after whole brain radiotherapy, premature atherosclerosis, cardiac dysfunction, or peripheral neuropathy.

E. Common Pitfalls and Side-Effects of Management.

The decision to treat with chemotherapy is made by a medical oncologist. The chemotherapy orders are to be written and signed only by a medical oncologist.

In the adjuvant setting, cisplatin-based doublet chemotherapy is given. The agents which can be combined with cisplatin include vinorelbine, etoposide, vinblastine, gemcitabine, docetaxel, or pemetrexed in nonsquamous NSCLC. Paclitaxel combined with carboplatin is an acceptable alternative regimen for patients with comorbidities or who are not able to tolerate cisplatin.

The histologic subtype is an important consideration in choice of systemic therapy. The preferred agents for first-line treatment of advanced or metastatic disease include carboplatin/albumin-bound paclitaxel, cisplatin or carboplatin plus docetaxel, etoposide, gemcitabine, paclitaxel, or vinorelbine, gemcitabine/docetaxel, and gemcitabine/vinorelbine. Bevacizumab/carboplatin/paclitaxel, bevacizumab/carboplatin/pemetrexed, and cisplatin or carboplatin plus pemetexed are options only for treatment of patients with nonsquamous histology. In select patients, single-agent therapy instead of combination therapy may be appropriate. Patients who test positive for an EGFR sensitizing mutation should receive first-line tyrosine-kinase inhibitor (TKI) therapy with erlotinib or afatinib, or gefitinib. Osimertinib is approved for patients with metastatic EGFR T790M mutation-positive tumor who have tumor progression on or after EGFR TKI therapy. Crizotinib is the preferred first-line therapy for patients with ALK rearrangements. Ceritinib is approved by the FDA as subsequent therapy for patients with ALK rearrangements who have progressed on or are intolerant to crizotinib. The option of participation in a clinical investigational study should be offered to eligible patients.

Maintenance therapy is an option for patients who achieve complete or partial response or stable disease after first-line therapy. Maintenance therapy is continued until progression of disease or unacceptable toxicity.

Patients who maintain an ECOG performance status of 0-2 and who have tumor progression either during or after first-line therapy can be considered for subsequent therapy with a systemic immune checkpoint inhibitor such as nivolumab or pembrolizumab. Treatment with other systemic single-agent chemotherapy is also an option.

Patients with an ECOG performance status of 3-4 and sensitizing EGFR mutations may be considered for systemic therapy with erlotinib or afatinib or gefitinib. Patients with ALK rearrangements and poor performance status may be considered for therapy with crizotinib. Best supportive care management alone remains an option for all ECOG performance status 3-4 NSCLC patients.

The list of potential side effects related to chemotherapeutic agents used to treat NSCLC is extensive. Patients who receive chemotherapy may experience asthenia, fatigue, appetite loss, metallic taste of foods, mucositis, myelosuppression, anemia, nausea, vomiting, diarrhea, constipation, renal toxicity, hepatic toxicity, electrolyte disturbance, peripheral sensory or motor neuropathy, autonomic dysfunction, amenorrhea, azoospermia, sterility, impotence, alopecia, immediate hypersensitivity reaction, and skin and nail changes.

Bevacizumab treatment can result in GI perforation. Use with caution in patients who have undergone recent surgery or an invasive procedure. Bevacizumab should be given at least 28 days after any surgery or invasive intervention. Fatal hemorrhage from hemoptysis can result and this has been observed in patients with cavity lung lesions. Patients with recent hemoptysis should not receive bevacizumab. An increased risk of arterial thromboembolic events has been associated with bevacizumab treatment.

EGFR TKI agents may inhibit the metabolism of warfarin by the liver P450 system.

Gefitinib, crizotinib, ceritinib, and osimertinib should be used with caution in patients at risk for developing QT prolongation.

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

Chemotherapy dose reduction or discontinuation of therapy may be indicated.

B. Liver Insufficiency.

Chemotherapy dose reduction or discontinuation of therapy may be indicated.

C. Systolic and Diastolic Heart Failure.

Chemotherapy is not recommended for patients with decompensated heart failure.

D. Coronary Artery Disease or Peripheral Vascular Disease.

An acute cardiac event within the preceding 6 months may preclude the use of certain chemotherapeutic agents.

E. Diabetes or other Endocrine issues.

Paclitaxel, docetaxel, and pemetrexed require dexamethasone pre-medication and this may raise blood glucose levels. The decision to treat with chemotherapy should be individualized.

F. Malignancy.

History of malignancy by itself is not a contraindication to treatment. Any prior treatment with surgery or radiation or systemic therapy must be taken into consideration. A patient with history of malignancy might be ineligible to participate in certain clinical investigational studies.

G. Immunosuppression (HIV, chronic steroids, etc).

There is no absolute contraindication for the use of chemotherapy. HAART therapy should be optimized in patients with HIV. Patients with chronic immunosuppression from co-morbid conditions are at increased risk to develop bacterial, viral, fungal or atypical infections during chemotherapy. Prophylactic anti-fungal, anti-viral, and antimicrobial therapy should be used as indicated.

H. Primary Lung Disease (COPD, Asthma, ILD).

Patients with primary lung disease are increased risk to develop

I. Gastrointestinal or Nutrition Issues.

Anorexia, nausea, vomiting, and diarrhea are common side effects of many chemotherapeutic agents. Patients may also develop altered sense of taste which affects appetite. It is important to avoid serum electrolyte imbalance, dehydration and weight loss during treatment with chemotherapy.

J. Hematologic or Coagulation Issues

Chemotherapy should not be given to patients with active, uncontrolled bleeding. Treat acute thromboembolic events according to standard guidelines. Warfarin has a potential drug-drug interaction with many chemotherapy agents. Patients should achieve adequate hematologic recovery based on established criteria before proceeding with additional cycles of chemotherapy. Dose modification or drug discontinuation is indicated for severe prolonged hematologic toxicity.

K. Dementia or Psychiatric Illness/Treatment.

Patients must be deemed competent to give informed consent to undergo treatment or have assigned power of attorney.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

Sign-out should be according to the standard format. The on-call physician should be immediately contacted if a patient undergoing chemotherapy is exhibiting an adverse reaction to treatment or there is any alteration in the treatment plan or any question concerning the chemotherapy order set or care of the patient.

B. Anticipated Length of Stay.

The anticipated length of hospital stay is dependent upon the admission diagnosis, the rapeutic intervention and hospital course.

C. When is the Patient Ready for Discharge.

The anticipated discharge is dependent upon the admission diagnosis, therapeutic intervention and hospital course.

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom.

An outpatient oncology appointment should be arranged within 1 - 2 weeks after discharge.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

The inpatient oncology service can provide management guidance.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

The inpatient oncology service can provide management guidance during the patient's hospitalization and make individualized appropriate recommendations for after-hospital disposition.

E. Placement Considerations.

Certain patients with documented advanced malignancy who are not candidates for active treatment or who elect best supportive care management alone may be considered for hospice placement.

F. Prognosis and Patient Counseling.

The estimated 5-year survival for patients with NSCLC is as follows: clinical stage IA - 50%; clinical stage IB - 43%; clinical stage IIA - 36%; clinical stage IIB - 25%; clinical stage IIIA - 19%; clinical stage IIIB - 7%. These estimates are based on data from the IASLC Lung Cancer Staging Project. The median overall survival for patients with stage IV disease who receive standard chemotherapy is 8-10 months. There is a survival advantage for patients with advanced or metastatic nonsquamous histology who receive first-line systemic treatment with bevacizumab or pemetrexed, patients with EGFR sensitizing mutations who receive TKI therapy, and patients with ALK rearrangements who receive crizotinib.

In addition to tumor staging, weight loss and performance status are important prognostic indicators. The Eastern Cooperative Oncology Group (ECOG) Performance Status Scale is commonly used to assess progression of disease and a patient's functional capacity.

ECOG PERFORMANCE STATUS:

Grade 0 - Fully active, able to carry on all pre-disease performance without restriction

Grade 1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work

Grade 2 - Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours

Grade 3 - Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours

Grade 4 - Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair

Grade 5 - Dead

Age by itself is not an independent prognostic indicator.

On average, women with advanced NSCLC live longer than men.

Solitary brain metastases, solitary adrenal metastases, the number of metastatic sites, presence of malignant pleural or pericardial effusion, liver metastases, low hemoglobin, high LDH, and low serum albumin level are prognostic factors.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

A patient undergoing chemotherapy should be assessed by his/her oncologist prior to each chemotherapy cycle to ensure adequate management of treatment-related side effects and need for dose modification. Prophylactic use of growth factor support may prevent recurrent severe neutropenia which increases risk for serious infection.

Patients with psychosocial issues may benefit from counseling by a trained clinical psychologist. Patients may benefit from an assessment by a social worker to identify and address special needs which are barriers to health care. A patient with demonstrated progression of disease who is not a candidate for additional disease-specific therapy can be considered for hospice.

VII. What's the evidence?

Schottenfeld, D, Pass, HI. "The etiology and epidemiology of lung cancer". Principles and Practice of Lung Cancer. Lippincott Williams and Wilkins. 2010. pp. 1-22.

Kwok, Y, Patchell, RA, Regine, WF, pass, HI. "Management of overt central nervous system metastases: brain and spinal cord". Principles and Practice of Lung Cancer. Lippincott Williams and Wilkins. 2010. pp. 920-921.

Wozniak, AJ, Gadgeel, SM, Pass, HI. "Clinical presentation of non-small cell carcinoma of the lung". Principles and Practice of Lung Cancer. Lippincott Williams and Wilkins. 2010. pp. 327-340.

Goldstraw, P, Crowley, JJ. "The International Association for the Study of Lung Cancer International Staging Project on Lung Cancer". J Thorac Oncol. 2006. pp. 281-286.

Travis, WD, Brambilla, E, Muller-Hermelink, HK. "World Health Organization classification of tumours". Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart. IARC Press. 2004. pp. 10.

Sculier, J-P, Chansky, K, Crowley, JJ. "The IASLC Lung Cancer Staging Project: The impact of additional prognostic factors on survival and their relationship with the anatomical extent of disease expressed by the 6th edition of the TNM Classification of Malignant Tumours and proposals for the 7th edition". J Thorac Oncol. vol. 3. 2008. pp. 457-466.

Gerber, DE, Schiller, JH, Skeel, RT, Khleif, SN. "Carcinoma of the lung". Handbook of Cancer Chemotherapy. Lippincott Williams and Wilkins. 2011. pp. 94-120.

Chrischilles, EA, Pendergast, JF, Kahn, KI, Wallace, RB, Moga, DC, Harrington, DP. "Adverse events among the elderly receiving chemotherapy for advanced non-small-cell lung cancer". J Clin Oncol. vol. 28. 2009. pp. 620-627.

Azzoli, CT, Temin, S, Aliff, T, Baker, S, Brahmer, J, Johnson, DH. "2011 focused update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small Cell Lung Cancer". J Clin Oncol. vol. 29. 2011. pp. 3825-3831.

Pisters, KMW, Evans, WK, Azzoli, CG, Kris, MG, Smith, CA, Desch, CE. "Cancer Care Ontario and the American Society of Clinical Oncology guideline for adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non-small cell lung cancer". J Clin Oncol. vol. 25. 2007. pp. 5506-5518.

Temel, JS, Greer, JA, Admane, S, Gallagher, ER, Jackson, VA, Lynch, TJ, Lennes, IT, Dahlin, CM, Pirl, WF. "Longitudinal perceptions of prognosis and goals of therapy in patients with metastatic non-small-cell lung cancer: Results of a randomized study of early palliative care". J Clin Oncol. vol. 29. 2011. pp. 2319-2326.

Howlader, N, Noone, AM, Krapcho, M. "SEER Cancer Statistics Review, 1975-2012, based on November 2014 SEER data submission, posted to the SEER web site, April 2015". National Cancer Institute. 2015. http://seer.cancer.gov/csr/19752012/.

Sandler, A, Yi, J, Dahlberg, S. "Treatment outcomes by tumor histology in Eastern Cooperative Group Study E4599 of bevacizumab with paclitaxel/carboplatin for advanced non-small cell lung cancer". J Thorac Oncol. vol. 5. 2010. pp. 1416-1423.

Scagliotti, G, Brodowicz, T, Shepherd, FA. "Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer". J Thorac Oncol. vol. 6. 2011. pp. 64-70.

Borghaei, H, Paz-Ares, L, Horn, L, Spigel, DR, Steins, M, Ready, NE. "Nivolumab versus docetaxel in advanced nonsquamous non-small cell lung cancer". N Engl J Med. vol. 373. 2015. pp. 1627-39.

Brahmer, JR, Tykodi, SS, Chow, LQ. "Safety and activity of anti-PD-L1 antibody in patients with advanced cancer". N Engl J Med. vol. 366. 2012. pp. 2455-2465.

Garon, EB, Rizvi, NA, Hui, R, Leighi, N, Balmanoukian, AS, Eder, JP. "Pembrolizumab for the treatment of non-small-cell lung cancer". N Engl J Med. vol. 372. 2015. pp. 2018-2028.

Pirker, R. "Third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cel lung cancer". Curr opin Oncol. 2015 Dec 30.

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