lung cancer

Definition:

The World Health Organization (WHO) defines lung cancer as tumors arising from the respiratory epithelium (bronchi, bronchioles, and alveoli).

OR

Lung cancer is a type of cancer caused by uncontrolled cell division of the respiratory epithelium (bronchi, bronchioles, and alveoli).

Normal structure and function of the lungs:

Lungs are 2 sponge, pyramid-like organs located in the chest. Each lung is divided into sections called lobes. The right lung has three lobes while the left lung has two lobes. The left lung is smaller than the right one because the heart on the left side takes up more room of the chest.

When you inhale air through mouth and nose it enters into lungs through trachea (windpipe). The trachea divides into tubes called bronchi, which enter the lungs and divide into smaller branches called bronchioles. At the end of bronchioles there are small tiny sacs called alveoli.

These alveoli absorb oxygen from the inhaled air into your blood and remove carbon dioxide from the blood when you exhale. Taking in oxygen and getting rid of carbon dioxide are your lungs main functions.

Lung cancers typically start in the respiratory epithelium of the bronchi and other parts of the lung such as the bronchioles or alveoli.

Label diagram of normal structure of lung

Branches of windpipes in diagram

Overview:

·      Lung cancer is a major cause of morbidity and mortality.

·     Lung cancer, which was rare before 1900 with fewer than 400 cases described in the medical literature is considered a disease of modern man.

·     By the mid-twentieth century, lung cancer had become epidemic and firmly established as the leading cause of cancer-related death in North America and Europe, killing over three times as many men as prostate cancer and nearly twice as many women as breast cancer. 

·     Despite major advances in the understanding and management of lung cancer, the overall 5-year survival rate for all types of lung cancer remains a dismal 15%.

·    The projected lifetime probability of developing lung cancer is estimated to be ∼8% among males and ∼6% among females.

Epidemiology of lung cancer:

·   In comparison to whites, the incidence of lung cancer is greater in African Americans and the mortality rate is greater in African American men but lower in African American women.

·  The incidence of lung cancer increases with age, with the peak age of diagnosis being between 55 and 65 years.

·        Approximately 225,000 individuals will be diagnosed
with lung cancer in the United States in 2017, and over 150,000 individuals will die from the disease.

·        Lung cancer is uncommon below age 40, with rates increasing until age 80, after which the rate tapers off.

Etiology:
  1)  Smoking:

a.  cigarette smoking is the main cause of lung cancer approximately 90% of lung cancers occur due to tobacco use.risk of lung cancer is in direct relation with cigarette smoked per greater the number of cigarettes smoked by the person greater will be the chance of lung cancer. Doctor describe the risk of lung cancer in term of pack-year of smoking history( number of cigarette smoked multiplied by the number of years smoked). if someone smoked two packs of cigarette/day for 10 years has a 20 paks history.so if we increased more 10 -pack- smoking history, those with 30-pack-year smoke history or more are considered to be at high risk for lung cancer. Out of 1 in 7 smokers will die due to lung cancer who smoked two or more packs per day.

b.  pipe and cigar smoking is also the main cause of lung cancer but its rate of causing cancer is less as compared to cigarette smoking. Person who smoked on a pack  of cigarette/day has a 25 times higher risk of lung cancer as compared to a nonsmoker, pipe

c.   Tobacco smoke contains over 4,000 chemical compounds, many of which have been shown to be cancer-causing or carcinogenic. The two primary carcinogens in tobacco smoke are chemicals known as nitrosamines and polycyclic aromatic hydrocarbons.

Smoker in action 

2)  Passive smoking:

 inhalation of tobacco smoke by nonsmokers who live among smokers is called passive smoking. Passive smoking is also the second main cause of developing lung cancer. About 24% of the non-smoker who resides near smoker has a risk of lung cancer. the risk of getting lung cancer is in direct relation with the degree of exposure.it's mean greater the degree of exposure to cancer greater will be the chances of developing cancer. About 7 thousands death occur each year in the US due to passive smoking.

3)  asbestos fibers exposure:

Asbestos fibers are silicate fibers that can persist for a lifetime in lung tissue following exposure to asbestos. The workplace was a common source of exposure to asbestos fibers, as asbestos was widely used in the past as both thermal and acoustic insulation. So asbestos is been banned in many countries like US  Canada china etc.asbestos not only causes lung cancer but also causes mesothelioma. asbestos worker with smoking is 9 fold chances of getting cancer. asbestos workers with passive smoking have 5 fold chances of getting cancer.

4)   Exposure to radon gas:

radon gas after smoking is the second main cause of lung cancer. radon gas emits a type of ionizing radiation that produces free radicals the leading cause of cancer. about 12% or 21,000 of the death are associated with radon gas exposure.

5)  Genetic factors or familial predisposition:

 most of lung cancer are due to smoking, exposure to asbestos fibers, exposure to radon gas, but the genetic factor is also an important factor while considering lung cancer. Although the exact ratio of developing lung cancer is not estimated yet.

6)  Lung diseases:

 lungs diseases like chronic obstructive pulmonary disease(COPD) increase the chances of  developing lung cancer 4 to 6 folds and pulmonary fibrosis increase the chances of developing lung cancer up to 7 folds.

7)  Prior history of lung cancer:

the chance of getting cancer in the second lung is high in record patients from lung cancer. about  1% to 2% per year chances of developing cancer in the second lungs of non-small lung cancers(NSCLCs) recovered patients. About 6 % per year chances of developing cancer in the second lung of small-cell lung cancer(SCLC) recovered patients.

8)  Air pollution:

 about 1% to 2% of the death associated with lung cancers are due to inhaling polluted air. greater exposure means greater chances of developing cancer.

Histological classification:

lung cancer is also called bronchogenic carcinoma because they arise from the epithelia of bronchi within the lungs. WHO classification system divides epithelial lung cancers or bronchogenic carcinoma into Two major cell types.

small-cell lung cancer (SCLC).

non-small-cell carcinomas (NSCLCs).

Principle of classification:

Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.

wheel diagram of types of lungs cancer with their microscopic appearance of epithelia in each type.

Small cell lung cancer (SCLC):

Small-cell carcinomas consist of small cells with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, absent or inconspicuous nucleoli, and a high mitotic count. SCLC may be distinguished from NSCLC by the presence of neuroendocrine markers including CD56, neural cell adhesion molecule (NCAM), synaptophysin, and chromogranin.

About 20% of lung cancer are small-cell lung cancer.it's very dangerous and rapidly growing as compared to non-small cell lung cancer.it's totally related to cigarette smoking about 99% of this cancer develops due to smoking. only 1% is due to passive smoking. sample appearance of small cell lung cancer is just like oat when examined under a microscope that’s why its also called oat cell carcinoma.                                                                                        

Non-small cell cancer:

Non-small cell lung cancer is the most common  lung cancers, secretarial for about 80% of all lung cancers. Non-small cell lung cancer  can be divided into three main types that are named based upon the type of cells found in the tumor:

• Adenocarcinomas are the most commonly seen type of NSCLC in the U.S. and comprise up to 50% of NSCLC. While adenocarcinomas are associated with smoking like other lung cancers, physicians see this type in nonsmokers who develop lung cancer, as well. Most adenocarcinomas arise in the outer, or peripheral, areas of the lungs.
• Squamous cell carcinomas were formerly more common than adenocarcinomas; at present, they account for about 30% of NSCLC. Also known as epidermoid carcinomas, squamous cell cancers arise most frequently in the central chest area in the bronchi.
• Large cell carcinomas sometimes referred to as undifferentiated carcinomas, are the least common type of NSCLC.

PATHOLOGY OF CELLS:

1. Squamous cell carcinoma	2. Adenocarcinoma	3. Large cell carcinoma
• Papillary • Clear cell • Small cell • Basaloid	• Acinar • Papillary • Bronchioloalveolar carcinoma • Nonmucinous • Mucinous • Mixed mucinous and nonmucinous or indeterminate cell type • Solid adenocarcinoma with mucin • Adenocarcinoma with mixed subtypes • Variants • Well-differentiated fetal adenocarcinoma • Mucinous (colloid) adenocarcinoma • Mucinous cystadenocarcinoma • Signet ring adenocarcinoma • Clear cell adenocarcinoma • Carcinomas with spindle and/or giant cells • Spindle cell carcinoma • Giant cell carcinoma • Carcinosarcoma • Pulmonary blastoma	• Variants • Large cell neuroendocrine carcinoma • Combined large cell neuroendocrine carcinoma • Basaloid carcinoma • Lymphoepithelioma-like carcinoma • Clear cell carcinoma • Large cell carcinoma with rhabdoid phenotype  • Variants • Large cell neuroendocrine carcinoma • Combined large cell neuroendocrine carcinoma • Basaloid carcinoma • Lymphoepithelioma-like carcinoma • Clear cell carcinoma • Large cell carcinoma with rhabdoid phenotype Typical carcinoid • Atypical carcinoid

                                                                                                                                                                                                                                            

Features of malignant neoplasm:

Cell type	Pathological features	Common chest x-ray finding
Squamous cell carcinomas	Keratin production, intercellular bridges	Central lesion with healor involvement,cavitation production
Adenocarcinomas	Gland formation, mucin production ,	Pripheralll lesion cavitaion may occur usually prerephral lesion,pneumonic like infilterate
Large cell carcinomas	Probably represent poorly differentiated no carcinoma	Usullay  prepheral lesion, larger then adenocarcinoma with tendency to cavity
Small cell carcinoma	Cell is twice the size of lymphocytes sizs	Central lesion, hilar mass common,early mediastinal involvement, no cavitation

CLINICAL MANIFESTATIONS:

• Over half of all patients diagnosed with lung cancer present with locally advanced or metastatic disease at the time of diagnosis.
• At the time of diagnosis, 16% of lung cancers are localized, 37% have regional spread, and 39% have distant metastases.
• The majority of patients present with signs, symptoms, or laboratory abnormalities that can be attributed to the primary lesion, local tumor growth, invasion or obstruction of adjacent structures, growth at distant metastatic sites, or a paraneoplastic syndrome.
• Location and extent of the tumor determine the presenting signs and symptoms.
• A lesion in the central portion of the bronchial tree is more likely to cause symptoms at an earlier stage as compared to a lesion in the periphery of the lung, which may remain asymptomatic until the lesion is large or has spread to other areas.
• The most common initial signs and symptoms include cough, dyspnea, chest pain, sputum production, and hemoptysis.
• Unfortunately, many patients with lung cancer also have chronic pulmonary and/or cardiovascular diseases (usually related to smoking), and such symptoms may  go unnoticed or be attributed to the concomitant disease.
• Many patients also exhibit systemic symptoms of malignancy such as anorexia, weight loss, and fatigue.
• Disseminated disease can cause extrapulmonary signs and symptoms such as neurologic deficits resulting from CNS metastases, bone pain or pathologic fractures secondary to bone metastases, or liver dysfunction resulting from tumor involvement in the live.

 Extrapulmonary sign and symptom associated with metastatic involvement:

·        Bone pain and pathologic fractures.

·        Liver dysfunction.

·        Neurologic deficit.

·        Spinal cord compression.

·        Hoarseness (secondary to laryngeal nerve paralysis).

·        Honers syndrome.

·        Phrenic nerve paralysis.

·        Pericardial effusion.

·        Tracheal obstruction.

   Clinical presentation of lung cancer:

·        Local sign and symptoms associated with primary tumor and or regional spread within the thorax.

·        Cough.

·        Hemoptysis,

·        Dyspnea.

·        Rust streaked or purulent sputum.

·        Chest shoulder or arm pain.

·        Wheeze or steroids.

·        Superior vena cava obstruction.

·        Plural effusion or pneumonitis.

·        Dysphagia (secondary to esopeghail compression).

  Paraneoplastic syndrome:

·        Weight loss.

·        Coughing syndrome.

·        Hyperkalemia (most commonly in squamous cell lung cancer).

·        Syndrome of inappropriate secretion of antidiuretic hormone ( most commonly in SCLC).

·        Pulmonary hypertrophic osteioortheropathy.

·        Clubbin .

·        Anemia.

·        Eaton lambert’s  mysanthytic syndrome.

·        Hypercoagulable state.

PREVENTION:

·        Diet was associated with lung cancer risk in several epidemiologic studies.

·        Increased intake of fresh fruit and vegetables lower risk in both men and women regardless of their smoking status.

·        The specific chemo preventive nutrients have yet to be identified, with
provitamin A carotenoids, particularly β-carotene, being the most
studied.

·        The effects of β-carotene on lung cancer risk were evaluated in three large-scale, randomized, chemoprevention trials, specifically ATBC (α-tocopherol β-carotene), CARET (Carotene and Retinol Efficacy Trial), and the Physicians’ Health Study.

·        Supplementation with α-tocopherol had no effect on lung cancer incidence or mortality, whereas β- carotene administration resulted in a higher incidence of lung cancer and increased mortality.

·        The chemopreventative effects of selenium, the EGFR inhibitor gefitinib, the cyclooxygenase-2 inhibitor celecoxib, and the farnesyl transferase
inhibitor lonafarnib are being evaluated.

   DIAGNOSIS:

·        A patient suspected to have lung cancer should undergo a multidisciplinary (including surgeons, radiologists, and medical oncologists) diagnostic evaluation. All patients must also have a thorough history and physical examination with emphasis on detecting signs
and symptoms of the primary tumor, regional spread of the tumor,
distant metastases, and paraneoplastic syndromes.

·        The patient’s performance status should be assessed to determine whether or not a patient may be able to withstand aggressive surgery or chemotherapy.

·        Weight loss, performance status and smoking history are key
findings that will direct treatment.

·        Baseline pulmonary function tests should also be obtained.

·        Chest radiographs, endobronchial ultrasound, CT scans, and
positron emission tomography (PET) scans are among the most
valuable diagnostic tests.

·        Chest radiography is the primary method of lung cancer detection, and may also be used to measure tumor
size, establish gross lymph node enlargement, and detect other
tumor-related findings, such as pleural effusion, lobar collapse, and
metastatic bone involvement of ribs, spine, and shoulders.

·        In addition, CT may be helpful in the evaluation of parenchymal lung
abnormalities, detection of masses only suspected on the chest
radiograph, and assessment of mediastinal and hilar lymph nodes.

·        PET scans are reported to be more accurate than CT scans in distinguishing malignant from benign lesions, detecting mediastinal
lymph node metastases, and identifying metastatic spread.

·        Most recently, the use of integrated CT-PET technology has been reported to improve the diagnostic accuracy in the staging of NSCLC over either CT or PET technology alone.

·        Pathologic examination of sputum cytology and/or tumor biopsy
by bronchoscopy, mediastinoscopy, percutaneous needle biopsy, or
open-lung biopsy may be necessary to establish the diagnosis of
lung cancer.

·        Mediastinal lymph node sampling via mediastinoscopy or dissection at the time of surgery is important to confirm the
presence or absence of lymph node involvement.

·        If mediastinal lymph nodes are found to be involved at the time of surgery, a complete lymph node dissection should be done.

·        Once the diagnosis is established, imaging of additional anatomic locations (e.g., brain) are obtained based on signs and symptoms of the patient and the anticipated treatment plan.

Picture of cancerous lung

STAGING:

The extent (or stage) of the tumor involvement is important
because it is used to select therapy, estimate the probability of cure
and survival, and facilitate comparison of the individual patient to large-scale clinical trials.

NON–SMALL CELL LUNG CANCER:

The World Health Organization has established a TNM staging
classification for NSCLC based on the primary tumor size and
extent (T), regional lymph node involvement (N), and presence or
absence of distant metastases (M).

 

SMALL CELL LUNG CANCER:

·        A two-stage classification established by the Veterans Administration Lung Cancer Study Group is widely used in the United States
to stage SCLC.

·        Limited stage is classified as disease confined to one hemithorax and to the regional lymph nodes.

·        All other disease is classified as extensive.

·        Approximately 60% to 70% of patients
initially present with extensive stage disease.

·        The initial pretreatment evaluation of a SCLC patient should include a medical history, a clinical examination including neurologic examination, laboratory tests (i.e., complete blood cell count with differential, serum electrolytes, liver function tests, calcium, lactate dehydrogenase, blood urea nitrogen, and serum creatinine), and chest radiography.

·        Additional testing is guided by suspicious signs or symptoms detected during the physical examination along with common sites of SCLC metastases.

·        Small cell lung cancer cells are detected in an extensive number of sites (e.g., liver 69%; adrenals 65%; bone and bone marrow 54%; pancreas 51%; brain 28% to 50%) during autopsy of patients diagnosed with SCLC.

Treatment of Non–Small Cell Lung Cancer:

·        If left untreated, most patients with NSCLC will die within 1 year of diagnosis.

·        Surgery, radiation therapy, and systemic therapy with
cytotoxic chemotherapy or targeted therapies are all used in the management of NSCLC patients.

·        The application of these various treatment modalities are determined by the stage of NSCLC and the patient’s comorbidities and performance status.

·        It is critical that the intent of treatment—whether curative or palliative—is clearly understood prior to starting treatment, as it will influence the aggressiveness of therapy.

·        Favorable prognostic factors for survival include early
stage disease, performance status ≤2 based on the Eastern Cooperative Group (ECOG) scale, no more than 5% unintentional weight loss, and female gender.

·        lists commonly used chemotherapy regimens for NSCLC and SCLC treatment.

Stages I and II Non–Small Cell Lung Cancer:

·        Surgical resection (pneumonectomy or lobectomy) is firstline treatment for patients with stages I and II (T1–2N0 and T1–2N1)
NSCLC with the exception of T3N0, for which the treatment is
discussed with stage III disease.

·        Overall, about 60% to 70% of patients with stage I and 40% to 50% of patients with stage II disease who undergo complete surgical resection survive 5 years without disease recurrence.

·        The most important prognostic factors for
patients undergoing surgical resection are the size of the tumor, the
presence or absence of lymph node involvement, and residual
tumor in the surgical margins.

·        Removal of the involved lobe of the lung (e.g., lobectomy) is the
recommended surgical procedure for stage I tumors, but some studies show that pneumonectomy may reduce the rate of local recurrences for patients with larger-size stage IB tumors.

·        Pneumonectomy, or removal of the entire lung (versus lobectomy), is the recommended surgical procedure for stage II disease with lymph node involvement (T1–3N1).

·        Despite complete resection, many patients with stage II
disease develop recurrent disease and die within 2 years.

Adjuvant Chemotherapy for Early Stage Lung Cancer:

Stages IIB and III Non–Small Cell Lung Cancer:

·        The prognosis for patients with either stage IIIA or IIIB NSCLC is
poor, with 5-year survival rates ranging from 10% to 40%, depend
overall survival when compared to preoperative radiation followed
by surgery.

·      The possible advantages of neoadjuvant therapy include earlier treatment of systemic disease, tumor regression that increases the likelihood of a complete surgical resection, improved patient compliance, and the ability to pathologically assess the response to chemotherapy, which may help guide future treatment.

· Neoadjuvant cisplatin-based doublet combinations are generally recommended.

·  Superior sulcus tumors (T3–4, N0–1) are treated with radiotherapy and concurrent chemotherapy followed by surgery, if resectable

·     If the tumor is not resectable, NCCN guidelines recommend treatment with definitive concurrent chemoradiation.

Unresectable Stage IIIB and Stage IV Non–Small Cell Lung Cancer:

•         About two-thirds of NSCLC patients present with advanced (i.e.,
unresectable stage IIIB and IV) disease at the time of diagnosis.

•         Most of these advanced tumors are not surgically resectable as a
result of disseminated (multiple sites) metastatic disease or metastatic sites that are not amenable to surgery.

•         Patients with single metastatic sites may undergo surgical resection of both the primary tumor in the lung and the metastatic site.

Single-Agent Chemotherapy:

•      Single-agent chemotherapy is an alternative in elderly patients or those with an ECOG performance status of 2.

•       First-line, single-agent chemotherapy has objective response rates of 5% to 25% with no significant effect on overall survival.

•      Complete responses are rare and those that do occur are of brief duration (i.e., 2 to 4 months).

•      Among the most active cytotoxic chemotherapy agents in NSCLC are cisplatin, carboplatin, docetaxel, paclitaxel, etoposide, gemcitabine, ifosfamide, irinotecan, topotecan, mitomycin, vinblastine, vinorelbine, and pemetrexed.
The EGFR inhibitor, erlotinib, is also active as a single agent, as discussed later in Human Epidermal Growth Factor Receptor Inhibitors.

Combination Chemotherapy:

•      Response rates for combination chemotherapy regimens are generally higher than for single-agent therapy, but improvement in overall survival rates has not been consistently observed.

•      Combination chemotherapy regimens that have consistently reported response rates exceeding 30% have used various combinations of cisplatin, carboplatin, gemcitabine, ifosfamide, or mitomycin, and vinblastine, vindesine, or vinorelbine.

Radiation Therapy:

•      Palliative radiotherapy with chemotherapy may be helpful in selected patients to control local and systemic disease and to reduce disease-related symptoms. Brain metastases are also commonly treated with radiotherapy; in the case of a solitary brain lesion, surgical resection may be used in conjunction with whole-brain radiation.

•      Adverse effects of radiotherapy frequently result in severe esophagitis, pneumonitis, skin desquamation, myelopathies, cardiac abnormalities, and pulmonary toxicity in the surrounding normal tissues.

•      Improved radiotherapy delivery techniques, such as multiple daily radiation fractions (hype rfractionated accelerated radiation therapy) and three-dimensional treatment planning, allow delivery of greater dosage fractions specifically to the tumor site while decreasing the  toxicity to surrounding normal tissues, as compared to standard radiotherapy.

•      A phase III trial randomized patients with unresectable
NSCLC to receive two cycles of PCb followed by either once-daily
radiation 64 Gy delivered in 32 2-Gy fractions or hyperfractionated
accelerated radiation therapy delivered three times a day for 15 days
with a total dose of 57.6 Gy (Gray Unit).

EVALUATION OF THERAPEUTIC OUTCOMES IN NSCLC PATIENTS:

•      Patients who have undergone surgical resection with or without
chemotherapy, radiation, or both, a physical examination and chest
radiography are recommended every 3 to 4 months for the first 2
years, then every 6 months for 3 years, and then annually

•       In addition, a low-dose spiral chest CT scan is recommended annually
to monitor for evidence of locoregional recurrence

•      Suspicious symptoms or physical findings (e.g., bone pain, visual abnormalities or headache, or elevated liver function tests) should prompt an evaluation to rule out distant metastases.

•      Tumor response to chemotherapy is generally evaluated at the
end of the second or third cycle and at the end of every second cycle
thereafter

•       Patients with stable disease, with objective response, or
with measurable decrease in tumor size (complete or partial
response) should continue until four to six cycles have been administered.38,39 Following initial therapy for NSCLC, patients must be monitored for evidence of disease recurrence.

Treatment of Small Cell Lung Cancer:

•      Combination chemotherapy regimens significantly increase
the median survival in SCLC patients

•      With treatment, median survival rates for patients with limited and extensive disease are 14 to 20 months and 9 to 11 months, respectively

•      Prognostic factors used to determine the appropriate therapy for SCLC patients include the stage of disease (i.e., limited vs. extensive disease) and performance status (e.g., an ECOG performance status of 0, or ability to carry out all normal activity without restriction)

•      Patients with a better performance status at the time of initial diagnosis also have an improved prognosis.

•      Additional prognostic factors that have been identified
as adverse prognostic factors in some studies include male gender,
older age, the total number of metastatic sites, development of
Cushing’s syndrome as a paraneoplastic manifestation, and abnormal lactate dehydrogenase.

SURGERY AND RADIATION THERAPY:

•      The role of surgery in SCLC has been evaluated in various clinical
trials of heterogenous populations who also received outdated chemotherapy regimens

•      Thus, the Agency for Healthcare Research and Quality Evidence Report stated that no conclusion can be drawn regarding the role of surgery in SCLC

•       In clinical practice, only the rare patient with small, isolated lesions undergoes surgery.

•      Because SCLC is considered to be a very radiosensitive
tumor, radiotherapy is used in combination with chemotherapy to
treat limited-disease SCLC or used alone for management of symptomatic metastases.

•      Radiotherapy decreases local recurrences in
patients with limited-disease SCLC with modest improvements in
survival.11,76 The optimal dose and scheduling of thoracic radiotherapy plus chemotherapy have not been fully defined.

•      Although survival is increased by twice-daily radiotherapy concurrent with chemotherapy, it is rarely used because of the inconvenience and the high incidence of severe esophagitis

•      Sequential therapy, in which radiotherapy begins after completion of chemotherapy administration, is inferior to concurrent chemoradiotherapy with the frequently used EP regimen

•      It is not clear whether to initiate thoracic radiotherapy with earlier cycles (i.e., cycle 1) compared to later cycles (i.e., cycle 6) of cisplatin-based chemotherapy

•      NCCN guidelines recommend the use of concurrent chemoradiotherapy over sequential therapy started with chemotherapy cycle 1 or 2 in limited-disease
SCLC patients.

•      NCCN: National Comprehensive Cancer Network.

CHEMOTHERAPY:

•      A number of cytotoxic agents have demonstrated significant single agent activity in chemotherapy-naive patients with limited- and extensive-disease SCLC, but the activity in recurrent or refractory SCLC is modest.

•      Cisplatin, carboplatin, etoposide, irinotecan, and topotecan are among the more commonly used chemotherapy agents in first-line treatment of SCLC patients.

•      Single-agent chemotherapy is inferior to doublet chemotherapy

•      In the United States, the most frequently used regimens in newly diagnosed patients are: PE (or EP): cisplatin (P) + etoposide (E); EC (CE): etoposide (E) + carboplatin (C); and IP: irinotecan (I) + cisplatin (P).

Second-Line Chemotherapy:

•      SCLC patients who relapse or progress after first-line chemotherapy
have a median survival of 4 to 5 months.

•      Unfortunately, when disease recurs, it is usually less sensitive to chemotherapy.

•      The agent of choice for second-line chemotherapy is often based on the length of time between completion of the induction chemotherapy regimen and relapse.

•      The likelihood of response is associated with the time from first-line therapy to relapse.

•      If this interval is less than 3 months, the patient has refractory SCLC and is unlikely to respond to second-line therapy.

•      In these patients, NCCN guidelines include
topotecan, irinotecan, CAV (cyclophosphamide, doxorubicin, and
vincristine), gemcitabine, paclitaxel, docetaxel, and vinorelbine as
treatment options. The original chemotherapy regimen is used for
those who have a long duration of disease control (i.e., >6 months
between induction chemotherapy and relapse).

EVALUATION OF THERAPEUTIC OUTCOMES IN SCLC PATIENTS:

•      The effectiveness of first-line therapy is evaluated after two to three cycles of treatment.

•      At this point, therapy is continued for patients with a complete or partial response or stable disease, and discontinued or changed to a non–cross-resistant regimen in patients demonstrating evidence of progressive disease.

•      The induction chemotherapy regimen is administered for four to six cycles if the SCLC disease is responsive.

•      In those with a complete response, PCI is offered as discussed above

•      After recovery from first-line therapy, follow up visits should occur every 3 months for years 1, 2, and 3, then every 4 to 6 months for years 4 and 5, then annually for patients with either a partial or complete response.

COMPLICATIONS AND SUPPORTIVE CARE:

•      Patients with lung cancer frequently have numerous concurrent medical problems.

•      Such problems may be related to invasion of the primary tumor and its metastases, paraneoplastic syndromes (see Clinical Presentation above), chemotherapy and radiotherapy toxicity, or concomitant disease states (e.g., cardiac disease, renal dysfunction, chronic obstructive pulmonary disease, asthma, or diabetes).

•      Depression is also common and sometimes persistent in patients with SCLC and NSCLC and should be treated. Identification, diagnosis, and treatment of the patient as a whole may improve the patient’s overall quality of life and tolerance to cancer treatments.

•      The chemotherapy regimens used in the management of lung cancer are intensive and are associated with a wide variety of toxic effects.

•      Nausea and vomiting may be severe.

•      Cisplatin-containing regimens require the use of aggressive acute and delayed antiemetic regimens containing a serotonin antagonist, dexamethasone and aprepitant.

•      Patients experiencing protracted nausea and vomiting may require intravenous hydration and nutritional support.

•      Myelosuppression is often the dose-limiting toxicity associated with chemotherapy. Granulocytopenia places patients at a high risk for serious infections.

•      Other toxic effects associated with these chemotherapy regimens include mucositis, anemia, nephrotoxicity, peripheral neuropathies, and ototoxicity.

•      Approximately 30% to 65% of advanced-stage NSCLC patients
will develop bone metastases, which may lead to significant bone pain, pathologic fractures, spinal cord compression, and hypercalcemia.

•      Zoledronic acid, an intravenously administered bisphosphonate, has been shown to reduce skeletal-related events in patients with bone metastases at a dose of 4 mg over 15 minutes infused every 3 weeks.

•      Although the data does not show a significant reduction in
skeletal-related events, time to first event is significantly increased thereby making zoledronic acid a viable therapy for patients with bone metastasis.

•      Patients receiving radiation therapy may experience complications including severe esophagitis, fatigue, radiation pneumonitis,
and cardiac toxicity.

•      These toxicities are usually more common and severe when radiation is combined with chemotherapy.

•      The patient’s baseline performance status and the degree of pulmonary dysfunction (e.g., chronic obstructive pulmonary disease from years of
tobacco use) must be considered in the decision of radiation dosage
and fractionation.

•      It is readily apparent that many lung cancer patients receive
complex pharmacologic regimens that may include chemotherapeutic agents, antiemetics, antibiotics, analgesics, anticoagulants, bronchodilators, corticosteroids, anticonvulsants, and cardiovascular agents.

•      Such regimens necessitate intensive therapeutic monitoring in order to avoid drug-related and radiotherapy-related toxic effects and to optimize therapeutic outcome for individual patients.

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