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Lung Cancer Cancer

Table of Contents
1 Disease Overview
        1.1 Risk Factors and Prevention
        1.2 Screening
        1.3 History, Symptoms and Signs
        1.4 Diagnosis and Tumour Assessment
2 Staging
3 Stage Grouping
4 Treatment Modalities
        4.1 Surgery
        4.2 Chemotherapy
        4.3 Metastatic NSCLC or Unresectable
        4.4 Treatment Algorithm for NSCLC
        4.5 Biologics
        4.6 Targeted Therapy
        4.7 Immunotherapy
        4.8 Radiation
        4.9 Small Cell Lung Cancer (20%)
5 Follow-up
6 Pivotal Trials
        7.1 Adjuvant Chemotherapy
        7.2 Metastatic Lung Cancer

    

Disease Overview

    Lung cancer is the most common cause of cancer-related deaths in Canada and US for both men and women, and most patients (approximately 85%) will die of the disease. There has been a dramatic change in management of advanced non-small cell lung cancer with targeted therapy, and more recently, immunotherapy.

Risk Factors and Prevention

    Most cases of lung cancer (85%) are caused by carcinogens in tobacco smoke; a small percentage of cases are caused by passive smoking or exposure to radon, radiation, or other chemicals.

    All patients should be encouraged to participate in smoking cessation. The cessation of smoking and encouraging smoking cessation is a critical preventive strategy. A healthy diet, high in fibre and vegetables, may be protective. Beta-carotene, vitamin A, or any of their derivatives does not appear to have a role in the prevention of lung cancer.

Screening

    Results of the National Lung Screening Trial showed benefit of low dose CT in reducing cancer mortality by 20% (NEJM 2011). However, there is still controversy in adopting CT chest as a screening tool in the general population. With that said, it should still be considered in patients who are smokers (National Lung Screening Trial Research Team et al., 2011). The best preventive strategy for lung cancer eradication is to never smoke, and for smokers, physicians should encourage smoking cessation.

History, Symptoms, and Signs

    Lung cancer is usually asymptomatic until the disease is advanced. When symptoms do occur, they vary depending on the location and size of the primary tumour (central or peripheral), any regional or metastatic spread, constitutional symptoms, such as fatigue, weakness, anorexia, weight loss, and the presence of various paraneoplastic syndromes. Symptoms associated with the primary tumour tend to be respiratory, whereas those associated with regional spread may be neurologic, due to nerve compression, or result from compression of the trachea, esophagus, or superior vena cava. The most common sites for metastatic disease in lung cancer are the lungs (both ipsilateral and contralateral), adrenal glands, liver, bone, and brain. Symptoms associated with metastatic spread may be related to brain, bone, and/or liver metastases.

Diagnosis and Tumour Assessment

    Diagnosis of lung cancer is made by evaluation of specimens obtained by bronchial biopsy or percutaneous needle biopsy and occasionally by sputum cytology. However, we should get adequate specimen for pathologic and molecular testing.

Pathologic Types

    Lung cancer is divided into non-small cell lung cancer (NSCLC), which accounts for approximately 80% of all lung cancers; and small-cell lung cancer (SCLC), at 20% of all cases.

    Molecular Subtype: All advanced lung adenocarcinoma need molecular testing of EGFR and ALK being tested at specialized pathology laboratory. Other mutations are assessed on clinical trials, and hopefully all targets can be assessed in each cancer type so patients can be treated with targeted therapy.

NSCLC includes the following cancer types, which are determined by histology:

  • Adenocarcinoma: arises from bronchial mucus glands, most common type (35–40% of all lung cancers), often located peripherally
  • Broncheoalveolar carcinoma: subtype of adenocarcinoma, arises from type II pneumocytes, grows along alveolar septa
  • Squamous cell carcinoma: 25–30% of all lung cancers, often located centrally
  • Large cell carcinoma: undifferentiated cancer, 10–15% of lung cancers, may be identified as adenocarcinoma or squamous cell carcinoma with electron microscopy

    SCLC is distinct from other types of lung cancer. This cancer behaves aggressively, growing rapidly and metastasizing early. Staging and treatment of SCLC differs from that of NSCLC.

    The suitability of the patient for a definitive resection depends on two factors: 1) preoperative evaluation and comorbid conditions need to be assessed to see whether they can withstand surgery and are operable candidates; and 2) stage of the lung cancer to assess if the cancer is resectable.

    A chest radiograph may be the initial investigation in a patient with persistent respiratory symptoms and risk factors for lung cancer. A complete history and physical examination is an important part of the workup, and laboratory tests include complete blood count, chemistry including electrolytes, renal function and liver function, sputum cytology (possibly for central tumours). Lung cancer is usually discovered on a chest X-ray.

    These investigations provide the information to determine the stage of lung cancer, resectability, and appropriate treatment options.

  1. CT of the chest and abdomen is necessary to evaluate the extent of the primary disease, mediastinal extension or lymphadenopathy as well as the presence or absence of other parenchymal nodules or metastatic disease.
  2. Bone scans should be obtained for patients with bone pain, chest pain, or an elevated calcium or alkaline phosphatase level.
  3. Positron emission tomography (PET) scans also are helpful in detecting distant metastases and a bone scan is not required for staging workup if a PET scan is done.
  4. CT or MRI of the head is recommended for stages II-IV, especially if surgery is being planned.
  5. Mediastinoscopy has long been considered the gold standard for mediastinal staging and has been recommended for mediastinal lymph nodes larger than 1 cm as detected by CT regardless of whether they appear positive or negative on PET scan. Patients with a normal mediastinum on CT whose lymph nodes also appear negative on PET scan probably do not need to undergo a preoperative mediastinoscopy but the lymph nodes need to be sampled at the time of surgery.
  6. EBUS (endobronchial ultrasound) is an evolving modality for assessment of mediastinal lymph nodes

Prognostic Factors

    Favourable prognostic factors for both NSCLC and SCLC are stage, performance status, lack of weight loss (<5%) and female sex. Predictive factors predict how a patient will fare with treatment. In lung cancer, EGFR mutation status is useful for predicting which patients are likely to derive the most benefit from EGFR TKIs, particularly responses and improved time to progression.

Staging

    Staging of non-small cell lung cancer gives information about the prognosis and helps in planning the treatment. The five year survival of stage I is 60-80%, compared to 0-5% in stage IV cancer. A large number of patients are diagnosed at advanced stage and are considered for palliative chemotherapy or targeted therapy. Lung cancer patients at diagnosis are seen by family physicians, internist and respirologist. Prompt referral after diagnosis is an important step in improving survival in lung cancer patients. As shown in the diagram, lung cancer often presents at advanced disease, but this can be reduced by screening high risk individuals for rapid diagnosis and treatments to improve survival.

    Treatment of lung cancer is multidisciplinary and needs to be discussed at tumour boards with the surgeons, radiation oncologists and medical oncologists. Patients require individualized plans that provide optimal outcome.

    Recommendations for seventh edition of TNM staging of NSCLC include additional cut-offs for tumour size with tumours larger than 7 cm moving from T2 to T3. Separate tumor nodule(s) in a contralateral lobe, tumor with pleural nodules or malignant pleural (or pericardial) effusion is now metastatic disease.

Stage Grouping


Treatment Modalities

Surgery

    Surgery is the main treatment for patients with stage I or II NSCLC and five year survival is 80-60%. These patients have no mediastinal disease and no local invasion. Spread beyond the primary tumour to mediastinal lymph nodes has a poorer prognosis (stage IIIA), and surgery in these patients is controversial. Surgery is rarely used in higher stages. Lobectomy is the standard surgical procedure for NSCLC. More extensive resection (pneumonectomy) may be required for some tumours, but this procedure is associated with greater operative mortality and post-operative morbidity. Video-Assisted Thoracoscopic Surgery (VATS) is minimally invasive and has a low level of morbidity and mortality. VATS has similar recurrence rates and survival statistics as open thoracotomy, as long as adequate resection is performed.

Chemotherapy

    Adjuvant chemotherapy consisting of a cisplatin-based combination is indicated for patients with stage II and IIIA NSCLC after surgical resection. Though controversial, it should be discussed with patients with stage IB disease, particularly higher-risk stage IB such as those with larger tumours (larger than 4 cm). Cisplatin and vinorelbine is the standard adjuvant therapy in early stage disease in Canada. Adjuvant chemotherapy confers a survival benefit 5-15% in resected stage II and IIIA NSCLC. NSCLC is moderately sensitive to chemotherapy, with two-drug, platinum-based combinations preferred over monotherapy.

    Optimal treatment of “non bulky” stage IIIA disease (e.g., small, single-station node) continues to evolve but optimally involves both systemic chemotherapy and local therapy (surgery and/ or radiation). For patients with multistation N2 disease or bulky N2 nodes (3 cm or larger) concurrent chemotherapy plus radiation therapy is considered standard of care. For non bulky N2 disease, a trimodality approach with chemoradiation followed by surgery can be considered, although patients requiring pneumonectomy (particularly right-sided pneumonectomy) had poor survival.

    Management decisions regarding stage IIIA NSCLC is multidisciplinary with surgeons, radiation and medical oncologist and done in thoracic tumour board. Curative-intent treatment of stage III A rarely IIIB NSCLC involves combined-modality treatment with chemotherapy and radiation therapy. Evidence from randomized trials suggests that concurrent chemotherapy and radiation therapy will result in the best survival, albeit at an increase in toxicity. The optimal chemoradiation schedule remains debatable; there is Level 1 evidence for concurrent chemoradiation with full-dose cisplatin and etoposide, and Level 2 evidence (based on randomized phase II data) supporting weekly low doses of paclitaxel and carboplatin with concurrent radiation followed by consolidation paclitaxel and carboplatin.

Metastatic NSCLC or Unresectable (stage IV)

    EGFR inhibitors should be considered standard of care in the first-line setting for patients with tumours harboring EGFR-activating mutations. Crizotinib is approved for the treatment of patients with ALK-positive.

    Cytotoxic chemotherapy improves survival and symptomatology for patients with metastatic NSCLC. Platinum-based doublet chemotherapy is considered standard of care and typically administered for four to six cycles for patients with good performance status (PS) if they do not have the mutation. Bevacizumab (15 mg/ kg every 3 weeks) prolongs survival when administered with carboplatin/paclitaxel in eligible patients with advanced nonsquamous cell carcinoma in a large randomized trial.

    In patients with stage IV of NSCLC, the tissue is sent to EGFR Canada for assessing EGFR and ALK mutations. If the tissue shows EGFR mutations, patients are offered targeted therapy such as gefitinib (Gefitinib is superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumour of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib.) If ALK is positive, patients are given crizotinib.

Second Line

    Second line chemotherapy is given on progression after first line chemotherapy. Chemotherapy is given to patients with performance status (ECOG (eastern cooperative oncology group) 1-2, that is, ambulating with minimal symptoms). Single-agent docetaxel (Taxotere®) at a dose of 75 mg/m2 every three weeks is recommended as second-line therapy for patients with recurrent or progressive NSCLC and adequate performance status (0-2).

    Two randomized phase III trial studies show benefit in overall survival (docetaxel to best supportive care [BSC], median survival was increased from 4.6 months to 7.5 months, (p=0.01 log rank), one-year survival from 12% to 37% (p=0.003 chi square). Single-agent pemetrexed (Alimta®) at a dose of 500 mg/m2 every three weeks is also an option for second-line therapy of recurrent or progressive disease, if available.

Biologics

    In selected subgroups of patients, EGFR-TKIs may improve survival when used as second- or third-line monotherapy. A monoclonal antibody to the EGFR receptor, when combined with first-line chemotherapy, has been shown to improve median survival. In addition, the combination of an antibody to vascular endothelial growth factor with first-line chemotherapy increases both response and median survival.

Targeted Therapy

    Gefitinib at a dose of 250 mg/day may be considered for second-line and subsequent therapy only for selected symptomatic patients who are not candidates for chemotherapy and for whom erlotinib is not available.

    Erlotinib at a dose of 150 mg/day is recommended as third-line therapy for patients with advanced recurrent or progressive NSCLC who maintain a good performance status following previous platinum-based and docetaxel (or pemetrexed) chemotherapy. Erlotinib is also an option for second-line therapy, particularly in patients who are not candidates for chemotherapy or for those with progression after first-line docetaxel-platinum chemotherapy.

Immunotherapy

    PDI inhibitors are showing promising results in clinical trials in advanced lung cancer results presented at ASCO 2015.

    Two randomized trials presented at ASCO show durable responses and less toxicity compared to docetaxel. Biomarkers are being standardized and the cost has to be manageable for the health care system.

    We have multiple options of treatment for lung cancer patients and the approach is multidisciplinary. Patients need to be encouraged to go on clinical trials.

    Two recent phase III randomized trials presented at the annual meeting at ASCO and published in NEJM2015.

Nivolumab vs docetaxel in previously treated advanced NSCLC HR 0.73 with overall survival benefit of 3.5 vs 2.8 months over docetaxel and toxicity profile was better compared to docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; p < 0.001).

    Brahmer, Speigel et al., presented a phase III randomized study of nivolumab vs docetaxel (checkMate 017) in previously treated advanced metastatic squamous NSCLC: response rate of 19% with nivolumab vs 9% with docetaxel and overall survival of 9.2 vs 6 (N Engl J Med 2015; 373:123-135). The risk of death was 40% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; p < 0.001).

Radiation

Radiation therapy is used in several ways in the treatment of NSCLC:

  • Alone in stage I and II disease, when surgical resection is not possible due to limited pulmonary reserve or serious comorbidities 20% 5 year survival
  • As adjuvant therapy in stage I and II disease where positive tumour margins are present
  • As adjuvant therapy in stage II and IIIA disease after complete resection to reduce local recurrence
  • Concurrently with chemotherapy in locally advanced (stage III) inoperable disease
  • Metastatic disease such as bone, brain and rarely liver

Small Cell Lung Cancer (20%)

    Small cell lung cancer tends to metastasize early and micrometastatic disease is present in patients at diagnosis. It is usually classified as 1) limited disease, which encompasses within one radiation port and is usually limited to the hemithorax and to regional nodes, including mediastinal and ipsilateral supraclavicular nodes; or 2) extensive-stage disease, which is usually defined as disease that has spread to other areas beyond the hemithorax. Small cell lung cancers demonstrate neuroendocrine features and is associated with paraneoplastic syndromes.

    A complete history and physical examination is an important part of the workup, and laboratory tests include complete blood count, chemistry including electrolytes, renal function and liver function. Common sites of metastases include brain, liver, bone marrow and CNS. Staging includes CT scan chest, abdomen and CT or MRI of the head.

    Prognostic factors in small cell lung cancer are stage of the disease, performance status serum LDH and gender. If the performance status is poor due to underlying disease, symptoms often disappear quickly with treatment and resulting in improvement in quality of life.

    In limited-stage SCLC, combination chemotherapy using cisplatin or carboplatin and etoposide, is being used with thoracic radiation as the main treatment modality. In limited-stage SCLC overall response rate is 75%-90% and a complete response rate of 50%. Median survival of limited disease is 14 months. If complete remission is achieved, prophylactic cranial radiation is offered.

    Extensive-stage SCLC is incurable but platinum-based combination chemotherapy prolongs survival and median survival is 9 months. New chemotherapy agents have generally not been active in SCLC. Both, relapsed and refractory SCLC have a poor prognosis and these patients are unlikely to respond to additional chemotherapy, but clinical trial participation is an option for these patients. Research on the use of biologics in SCLC lags behind that in NSCLC.

Follow-up

    The optimal follow-up schedule for lung cancer survivors has not been determined and is at the discretion of the physician.

    In lung cancer early referral to palliative and supportive care improves survival in advanced lung cancer. Goals of care need to be discussed during visits in the clinics. A family meeting is valuable for family to understand the palliative nature of the disease ask pertinent questions and to make important plans before the condition progresses. The SPIKE model should be followed, and the physician should discuss with the patient a care plan that is personalized to them. The discussion should also include questions, as follows: is the patient comfortable, what is their perception of the disease and treatment, are they prepared to talk about the disease, what do they understand, etc. In summary, physicians need to show compassion and support, and summarize the plan of care for their patient. Physicians should focus on goals of care, prevent and treat toxicity, and provide support to patient and family.


Pivotal Trials

Adjuvant Chemotherapy

Keller SM, Adak S, Wagner H, et al. A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group. N Eng J Med. 2000; 343(17):1217-22

Scagliotti GV, Fossati R, Torri V, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell Lung cancer. J Natl Cancer Inst. 2003; 95(19):1453-61

Metastatic Lung Cancer

Shaw AT, et al. Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer.N Engl J Med. 2013; 368:2385-2394.

Paz-Ares L, et al. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial.Lancet Oncol. 2012; 13(3):247-55.

Zukin M, et al. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2.J ClinOncol. 2013;31(23):2849-53.


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