1
Lithuanian University of Health Sciences
MEDICAL ACADEMY FACULTY OF MEDICINE
Oz Yael
Adverse Reactions During Systemic Lung Cancer Treatment Department of Pulmonology
Scientific supervisor:
Prof. Skaidrius Miliauskas
Kaunas, Lithuania
2019-2020
2
Table of contents
1. Summary
2. Conflict of Interest 3. Acknowledgment
4. Ethics Committee Study Permission 5. Introduction
6. Aims and Objectives 7. Literature Review
7.1 Classification 7.2 Risk Factors 7.3 Diagnosis
7.4 Systemic Treatment of Lung Cancer
7.5 Current Systemic Agents Treating Lung Cancer
7.6 Adverse Reactions of Systemic Treatment of Lung Cancer 8. Research Methodology and Methods
9. Results 10. Discussion 11. Conclusions 12. References
3 5 6 7 8 9
10 11 12 13 14 17 20 21 28 29 30
3
1. Summary
Title - Adverse reactions during systemic lung cancer treatment.
The aim of the thesis - Investigate, analyse and compare the adverse drug reactions (ADR) of different systemic lung cancer treatments in patients with lung cancer in the pulmonology department of “Kauno Klinikos” hospital.
Objectives of the study- 1. To collect the patient’s diagnosis, treatment and ADRs to systemic treatment of NSCLC in the pulmonology department of “Kauno Klinikos” hospital.
2. To evaluate the results regarding group-specific adverse drug reactions and determine the agent with the highest prevalence and severity of ADRs in each group in patients with different types of systemic treatment for NSCLC in the pulmonology department of “Kauno Klinikos” hospital. 3. To compare and determine the overall statistical significance of the results on ADRs, agents with the highest prevalence and severity of ADRs between patients treated with different types of systemic drug regimens for NSCLC in the pulmonology department of “Kauno Klinikos” hospital.
Methodology- Prospective study of 64 patients, who were diagnosed and confirmed histologically with stage III/IV NSCLC. The study was conducted over a 3-month period (Nov.2019-Jan.2020). The patients were divided into 3 groups according to the systemic therapy they received (chemotherapy, immunotherapy and target therapy). Each patient has been evaluated for adverse effects after 1 cycle of therapy by 11-item paper questionnaire derived from CTCAE version 5.0. and lab results. The data has been collected, organised and analysed.
Results- The results of the research revealed that patients undergoing chemotherapy, experienced the most of adverse effects (49.65%). Patients undergoing target therapy experienced the least of adverse effects (25.5%). Among the 34 patients, fatigue was the most common adverse effect (n=29, 85.3%) reported. Headache was reported only by 2 patients (5.9%). Among 30 patients, more than 50%
experienced anaemia grade 1.
Conclusions- 1. Systemic assessment including questionnaires are a key factor to improving data collection of side effects from patients. Due to lack of communication between physicians and patients or some physicians are less likely to ask about unexpected toxicities. 2.By using descriptive analysis, it was found that chemotherapy is more likely to cause adverse effects during treatment of NSCLC. 3.The adverse toxicities: nausea, fatigue, pain, alopecia and paraesthesia may occur in all types of systemic treatment of NSCLC and are not related to specific treatment. 4.It can be concluded that target therapy yields a favourable toxicity profile. It suggests that target therapy may be a safe treatment approach in patients with NSCLC.
4 Abbreviations
ADR- adverse reaction SCLC- small cell lung cancer NSCLC- non small cell lung cancer VEGF- vascular endothelial growth factor EGFR- epithelial growth factor
ALK- Anaplastic large cell lymphoma kinase gene TKI- Thyroid kinase inhibitors
HER2- Human epidermal growth factor 2 PD-1-Programmed death-1
PFS- Progression-free survival
5
2. Conflict of interest
There are no conflicts of interest.
6
3. Acknowledgment
I would like to thank Professor Skaidrius Miliauskas, Head of pulmonology department in "Kauno Klinikos" hospital for his expert advice, guidance and suggestions that helped me to complete my master thesis.
7
4. Ethics committee study permission
The master thesis approved by LSMU bioethics center.
Registration number: BEC-MF-100
8
5. Introduction
Lung cancer is among one of the foremost common malignant tumours and leading cause for cancer deaths around the world. There are 2 types of lung cancer: small cell lung cancer (SCLC) which accounts for 5%-15% of all cases and non-small cell lung cancer (NSCLC) which accounts for 80-85% of all cases of lung cancer [1,2].
The main risk factor of lung cancer is tobacco smoking which depends on the amount of cigarettes smoked per day and the duration of smoking. However, many cases of lung cancer can occur in non-smokers due to pollution, genetic factors and occupational exposures [3–5].
Nowadays, the diagnosis of lung cancer is confirmed by clinical examination of the patient’s symptoms (cough, dyspnoea, pain, etc.), imaging, tissue examination and histological confirmation. The treatment of lung cancer is decided by staging of the tumour and the functional evaluation of the patient (age, performance status, comorbidity). Currently the stage classification is the 8th TNM system [6,7].
After establishing the diagnosis and staging of the lung cancer, the acceptable treatment can be chosen, under the aim of removing the tumour cells without destroying the normal cells. Treatment options may include surgery, radiation and systemic treatment (chemotherapy, immunotherapy, target therapy). These treatments are often used on their own or together to treat lung cancer. The therapeutic agents differ by their mechanism of action, effects, indications and adverse reactions [1].
Toxicities are common difficulties during the systemic treatment of lung cancer. The extent of severity of adverse reactions depends on the therapeutic agent and dose, the patient’s age, physical and mental performance and comorbid diseases. Toxicities can be experienced on multiple organs and systems as cardiac, pulmonary, gastrointestinal, nervous system, skin and hair follicles. Timing and duration of toxicities are very important. Some toxicities can occur immediately after therapy administration or some are delayed and more long-term.
In some cases, adverse reactions are often fatal or impair the patient’s function. Therefore, there is a need to discontinue the systemic treatment and change to a different therapeutic agent [1,2].
9
6. Aims and Objectives
Aim: To investigate, analyse and compare the adverse drug reactions (ADR) of different systemic lung cancer treatments in patients with lung cancer at the Pulmonology Department of “Kauno Klinikos”
hospital, Lithuania.
Objectives:
1. To collect the patient’s diagnosis, treatment and ADRs to systemic treatment of NSCLC in pulmonology department of “Kauno Klinikos” hospital, Lithuania.
2. To evaluate the results regarding group-specific adverse drug reactions and determine the agent with the highest prevalence and severity of ADRs in each group of patients with different types of systemic treatment for NSCLC in the Pulmonology Department of “Kauno Klinikos” hospital, Lithuania.
3. To compare and determine the overall statistical significance of the results on ADRs, agents with the highest prevalence and severity of ADRs between patients treated with different types of systemic drug regimens for NSCLC in the Pulmonology Department of “Kauno Klinikos”
hospital, Lithuania.
10
7. Literature review 7.1. Classification:
Lung cancer is divided into 2 types supported histology:
7.1.1. Small cell lung carcinoma (SCLC), accounting for ~15% of all lung cancer.
Is derived from neuroendocrine cells of the lung. The cancer is highly aggressive (undifferentiated) and tends to be in centre of mediastinum. Microscopic examination shows tumour cells that are small in size (compared with other types of lung cancer), have a round uniform shape with scanty cytoplasm. High mitotic rate characterises the cancer. The most vital neuroendocrine markers are CD56, synaptophysin and chromogranin [3–6].
7.1.2. Non-small cell lung carcinoma (NSCLC), accounting for ~85% of all lung cancers and classified into 3 subtypes:
Squamous cell carcinoma: compromises 20%-30% of all lung cancers. It tends to arise from the main bronchi, within the centre of the lung and may form cavities. The malignant tumours are strongly associated with excessive smoking. In microscopic examination tumour cells are characterised by keratinisation forming keratin pearls and intracellular bridges. The tumour cells do not produce mucin [3–6].
Adenocarcinoma: is the most common lung cancer and compromises 35%-45% of all lung cancers. The tumour tends to arise within the periphery of the lung. It is associated with smokers and non-smokers. Microscopic examination of tumour cells characterised with glandular structure, producing mucin [3–6].
Large cell carcinoma: is a highly anaplastic undifferentiated tumour. This type of tumour shows no characteristics of carcinoma, glandular or neuroendocrine cells and compromises 5%-10% of all lung cancers. The tumour is commonly located within the periphery of the lung and is strongly related to smoking [3–6].
Fig.1 SCLC squamous cell adenocarcinoma carcinoma
11
7.2. Risk factors:
7.2.1. Smoking
Is the most common risk factor for lung cancer. Factors which influence the risk are the number of cigarettes smoked per day and the duration of smoking. Tobacco smoke consists of a high number of carcinogens, such as aromatic amines, N-nitrosamines, radon, benzene, vinyl chloride, arsenic, etc. The carcinogens create covalent bonds and bind to DNA, inhibiting the repair mechanism of DNA, causing mutations. Moreover, some carcinogens are able to down-regulate tumour suppressor genes and lead to uncontrolled proliferation of cells. Non-smokers in the vicinity of smokers increase their risk of developing lung cancer by 20%.
All types of lung cancer are related to smoking. Small cell lung cancer and squamous cell carcinomas are most associated with smokers. In contrast, adenocarcinoma of the lung is most common in non-smokers [4,6,7].
7.2.2. Occupational Carcinogens
Several occupational substances can cause lung cancer, including exposure to asbestos, arsenic, beryllium, silica, radon, nickel, coal, etc.
Asbestos is the most common occupational cause of lung cancer [7,8].
7.2.3. Air pollution
Air pollution has been related to an increased risk of lung cancer, especially in developing countries. The main source of air pollution is from vehicle emissions, which produce carcinogenic components such carbon monoxide, radon, sulphur dioxide, benzene and metals. Studies show that exposure to air pollution can cause DNA damage, mutations in somatic and germ cells and other chromosomal abnormalities in individuals [6-8].
7.2.4. Genetic factors
The assumption that genetic factors related to the danger of lung cancer is supported by the incidence of lung cancer among non-smokers and having a family history of lung cancer. A meta- analysis involving 32 studies showed increased risk of developing lung cancer in persons with a family history of lung cancer, with an increased risk also present in non-smokers [7].
Lung cancer is associated with mutations in genes related to DNA repair enzymes and mutations in genes related to metabolism and accumulation of carcinogens in lung tissue. Genome studies have found many variations along the chromosomes (ex; 5p15.33, 6p21.33) that are associated with the risk of lung cancer. Individuals with a genetic predisposition are at higher risk if they smoke tobacco [7,8].
12
7.3. Diagnosis:
Most patients with lung cancer are symptomatic at the time of diagnosis. Symptoms can be caused by the primary tumour, extension of the tumour and distant metastasis.
Table 1. Symptoms of lung cancer
Symptoms due to primary tumor Symptoms due to distant metastasis Symptoms Range of frequency (%) Organ
Cough 8-75 Bone(<25%) Pain, fracture, high ALP
Hemoptysis 6-35 Liver(<60%) Hepatomegaly, anorexia,
weight loss
Dyspnea 3-60 Brain(<10%) Headache, vomiting, seizures
Chest pain 20-49 Lymph node(<20%) Lymphadenopathy,
Fatigue 0-20 Adrenal gland(<5%) Adrenal insufficiency
Wheezing/stridor 0-2
Symptoms of lung cancer [9–11]
Diagnosis of lung cancer requires 3 steps: tissue examination and histological confirmation, staging of the tumour and functional evaluation of the patient.
7.3.1. Tissue examination and histological confirmation
Tissue examination is required to differentiate between SCLC and therefore the subtypes of NSCLC. The foremost diagnosis allows us to focus on optimising the patient’s course of therapy. The choice of diagnostic method for obtaining a tissue sample depends on the location, type and size of the tumour. For central tumours, the diagnostic methods for gathering samples are sputum cytology, bronchoscopy brushing and transbronchial needle aspiration. For peripheral tumours, the diagnostic method is CT- guided transthoracic needle aspiration [9,10].
7.3.2. Stage
Clinical staging of lung cancer is fundamental to planning therapy. Tumour staging provides a characteristic description of the primary tumour, extension and invasion to nearby tissues and distant metastasis. The stage is based on clinical staging (information taken before treatment, including: lab results, minimal invasive procedures such as bronchoscopy and CT/PET imaging) and pathological staging (information taken after surgical resection).
Stage classification is predicated on TNM system. The foremost updated version (8th version) published by the Union for International Cancer Control (UICC).
13 7.3.3. Functional evaluation
Some patients are unable to tolerate or survive a number of types of therapy for lung cancer, due to patients’ characteristics (advanced age, comorbidities and nutrition status).
Lung function needs to be evaluated before starting treatment. Pulmonary function testing (spirometry) and carbon monoxide diffusion are tests used for evaluation. A patient with a forced expiratory volume of more than 80% (FEV1 > 80%) and a diffusion capacity of more than 80% can continue to undergo therapy without further evaluation [9,10].
7.4. Systemic treatment of lung cancer.
Chemotherapy treatment of lung cancer was the first systemic treatment and is still the gold standard therapy option today, despite its effect on the median overall survival being around 1 year. This has encouraged the research and development of other treatment methods, particularly target and immunotherapy.
Treatment selection depends on the patient’s status (age, physical and psychological, comorbidity) and diagnosis characteristics (tumour markers, histology) [13,14].
• Chemotherapy: This approach remains the primary treatment for the majority of patients. First line chemotherapy treatment is platinum based (ex. Cisplatin), which may be used on its own or in combination with other treatment modalities used for lung cancer.
• Target therapy: The mechanism of action focused on inhibition of VEGF, EGFR or ALK.
Combined therapy with chemotherapy shows an improved outcome in patients with advanced lung cancer.
• Immunotherapy: The mechanism of action of these drugs is directed against cytotoxic T lymphocyte-associated antigen 4 (CTLC4), programmed death-1 (PD-1), and PD-L1 ligands.
Immunotherapy is given as first line therapy (superiority to chemotherapy) in patients with PD-L1 expression in 50% or more in the tumour cells [13,14].
14
7.5. Current systemic agents treating lung cancer
7.5.1. Chemotherapy agents
Apply their effects by disrupting the cell cycle in several points.
Cancer cells have the ability to proliferate and grow without control due to loss of suppressor genes and by obtaining proto-oncogene genes.
The cell cycle has 4 stages: mitosis(M), gap(G)1, synthesis(S) and gap(G)2. The chemotherapy agents are interfering with the stages, where there is no creation of DNA and proteins, leading to the apoptosis of the cell. Chemotherapy drugs differ by mechanism of action on the cell cycle [15,16].
7.5.1.1. Platinum compounds (Cisplatin, Carboplatin, Oxaliplatin).
These drugs are a subgroup of alkylating agents and form covalent bonds with DNA, break the DNA strands and form inter-strand DNA cross-linking, preventing the cell cycle and causing apoptosis.
Cisplatin is the most common chemotherapeutic drug used for solid tumours. The DNA damage in certain tumours caused by cisplatin is often repaired by the excision repair enzyme ERCC1found in these tumours. But due to the absence of ERCC1 in non-small cell lung cancers, cisplatin has been shown to improve the 1-year overall survival rate in patients treated with cisplatin following surgical resection.
The platinum compounds is preferred for use on its own due to adverse reactions in patients. However, due to the possible development of resistance, cisplatin is used in combination with other chemotherapy or target agents [1,4,15,16].
7.5.1.2. Anti- metabolites agents (Methotrexate, Gemcitabine)
These drugs work on the S stage. The agents are structural and have a resemblance to purines and pyrimidines which inhibit enzymes in DNA synthesis. Anti- metabolites agents are subdivided into: pyrimidine analogues (Gemcitabine, 5-Fluorouracil) and Anti-folates (Methotrexate).
Gemcitabine has shown high activity against NSCLC by inhibiting ribonucleotide reductase, a key enzyme in DNA synthesis. However, this drug is not the first line therapy treatment due to high cytotoxic effects on patients and malignancies which have developed resistance against the drug.
Currently, this drug is used in combination with other drugs (ex; cisplatin) for NSCLC patients [1,15,16].
7.5.1.3. Tubulin binding drugs
These drugs act on the M stage. The agents interfere with microtubule assembly and performance by binding to tubulin. There are 2 subclasses: vinca alkaloids (Vincristine, Vinorelbine) and taxanes (Paclitaxel, Docetaxel).
Paclitaxel is commonly used as the first line treatment for NSCLC. It binds to tubulin and hyper- stabilisation microtubules, which do not allow the mitotic spindle to break down. Paclitaxel is commonly used with other chemotherapeutic agents to overcome drug resistance [1,15,16].
7.5.1.4. Topoisomerase inhibitors
15 These are a group of enzymes responsible for DNA uncoiling during DNA replication and transcription. Topoisomerase I inhibitors (Topotecan) Topoisomerase II inhibitors (Etoposide).
These drugs are not commonly used but have shown an increase in the overall survival rate when used in combination with VEGF-I [4,15,16].
7.5.2. Target therapy
Target therapy acts on genetic variations and signalling pathways which lead to proliferation and growth of the cancer cells. Target therapy is used to improve patient outcomes and quality of life.
7.5.2.1. EGFR tyrosine kinase
The epidermal growth factor receptor (EGFR/ ErbB1/ HER1) is one of the receptor tyrosine kinases. The EGFR (extracellular receptor) is the first signal in the downstream intracellular pathway (PI3K/AKT and RAS/RAF/MAPK) which controls cell proliferation, growth and apoptosis. Mutations of EGFRs can lead to abnormal activation of this receptor, leading to uncontrolled cell proliferation and growth. EGFR is more than 50% overexpressed in NSCLC. Target therapy works by inhibiting these pathways by receptor monoclonal antibodies (mAB) or small molecule TKI inhibitors [17,18].
Thyroid kinase inhibitors (TKI): Gefitinib and Erlotinib
These agents are ATP inhibitors for the tyrosine kinase domain of EGFR causing blockages of the intracellular pathway. Gefitinib can be used as the first line treatment for NSCLC patients with approved EGFR mutation, especially for patients with contraindications to chemotherapy therapy. Target therapy can also be given to patients with unknown EGFR status, combined together with platinum-base chemotherapy or as a second line therapy treatment after chemotherapy treatment has failed [1,18].
Anti-EGFR monoclonal antibodies (Cetuximab, Necitumumab, Panitumumab)
mAB are competitive inhibitors to the extracellular domain of EGFR receptor. These agents are less effective than TKI. Some studies have shown an improvement in the overall median survival rate with cetuximab and platinum-based chemotherapy versus chemotherapy alone [18].
7.5.2.2. Anaplastic large cell lymphoma kinase gene (ALK)
ALK dislocation is rare and found only in 4%-7% of NSCLC patients, especially in the younger population. The ALK fuses with echinoderm microtubule-associated protein-like protein 4 (EML4) within chromosome 2. The ALK-EML4 fusion activates ALK kinase, causing malignant proliferation.
ALK inhibitor (Crizotinib) is superior in comparison to chemotherapy for the treatment of ALK-positive advanced NSCLC. Studies show that crizotinib therapy has a far better median overall survival rate and is also safer [4,17,18].
16 7.5.2.3. KRAS gene
KRAS is an oncogene that is observed in many neoplasms (colon cancer, lung cancer, pancreatic cancer). KRAS activates tyrosine kinase in the extracellular receptors and sends a signal to the nucleus by RAS-RAF- MAPK and PI3K-AKT-mTOR pathways. The KRAS gene produces GTPase which cleaves GTP, regulates cell signal and proliferation. KRAS mutation leads to unregulated cell proliferation. Patients with KRAS mutations are usually smokers (KRAS mutation in lung cancer is about 30% in smoker patients and 5% in non-smokers).
Selumetinib (MEK1/MEK2 inhibitor). The drug inhibits one of the KRAS downstream pathways. Studies with selumetinib combined with docetaxel have shown improvement in KRAS positive patients [18,19].
7.5.2.4. Vascular endothelial growth factor (VEGF)
Angiogenesis is regulated by some factors (VEGF, FGF and PDGF). Anti-angiogenic agents disrupt the blood supply to tumours, inhibiting growth.
Bevacizumab is a monoclonal antibody. It works by inhibiting VEGF, which slows down the development of the blood vessels. First line therapy for NSCLC is including a combination of platinum- based chemotherapy and bevacizumab. VEGF inhibitors are not used for squamous-cell carcinomas due to pulmonary toxicity which can cause heavy haemoptysis [4,17,18].
7.5.2.5. Human epidermal growth factor 2 (HER2)
Around 30% of NSCLC overexpress HER2, but only 3% carry the HER2 mutation. The HER- 2 mutation is common in women and non-smokers. Some trials with Trastuzumab (monoclonal antibody against HER-2) and chemotherapy have shown a good response, but it is still under investigation [4,17,18].
7.5.3. Immunotherapy
Functioning immunity consists of an anti-tumour immune response which is initiated by the recognition of the tumour antigens by T lymphocytes followed by the binding of T-cell receptors (TCR) to peptide-major histocompatibility complex (MHC) on antigen presenting cells (APCs), allowing T cell activation. Tumour cells activate immune resistance by utilising immune-checkpoints mechanisms, causing the inactivation of T cells [20].
7.5.3.1. PD-1 inhibitor
Programmed death-1 (PD-1) is an immune checkpoint receptor expressed on activated T cells.
The interaction between PD-1 with PD-L1/PD-L2 on APCs on some normal and tumour cells, causes T cell inactivation. This allows for the control and limiting of T cell activity and the inflammatory response extent.
17 Pembrolizumab / Nivolumab are antibodies that bind to PD-1 receptors, preventing its interaction with PD-L1/L2 and preventing T cell inactivation, allowing for the prolongation of the immune response against tumour cells. Clinical investigations have shown the superiority of PD-1 inhibitors as the first line treatment for NSCLC patients who are PD-1L positive. The tests showed that PD-1 inhibitors provide longer progression-free survival (PFS) and less adverse reactions than the platinum-based chemotherapy in this group of patients. Pembrolizumab increases the median PFS to around 10 months compared to 6 months in the chemotherapy group [19,20].
7.5.3.2. PD-L1 inhibitor (Atezolizumab)
Usually Atezolizumab is used in combination with various first-line chemotherapy drugs for locally advanced or metastatic NSCLC [19].
7.6. Adverse reactions of systemic treatment of lung cancer
Adverse reactions are a common problem during systemic treatment of lung cancer. Adverse reactions vary with the therapeutic agent and dose, the patient’s age, physical and mental performance, and prevalence of comorbid diseases.
Adverse reactions can result in the discontinuation of treatment due to risks for the patient and poor quality of life. Adverse reactions can have an effect on multiple organ systems such as the cardiac, pulmonary, gastrointestinal, nervous system, skin and hair follicles [21,22].
7.6.1. Haematological effects
Haematological toxicity is more common in patients undergoing chemotherapy treatment than target/immunotherapy. Chemotherapy may interfere with the activity of proliferating haematopoietic precursor cells.
Anaemia is the most common haematological effect observed but thrombocytopenia and leukopenia may also occur in many patients. Clinical manifestations may include: weakness, fatigue, purpura, petechia and an increase risk of infection [2,21].
7.6.2. Gastrointestinal (GI) effects
GI effects (nausea and vomiting) usually have a rapid onset (1-4 hours). GI effects are common during chemotherapy treatments. The chemotherapy substance irritates the emetic centre causing the body to expel the toxic substance.
Diarrhoea is a common side effect for all kinds of systemic lung cancer agents. Diarrhoea can cause dehydration, electrolyte and albumin loss which can affect the patient’s function. Diarrhoea is prevalent in 20%-30% of patients with TKI (Erlotinib, Gefitinib) treatment due to altered gut motility.
18 Patients undergoing anti-PD-1/PD-L1 therapy may experience (1%-3%) diarrhoea and colitis which can cause abdominal pain and bloody diarrhoea.
Constipation is less common than diarrhoea and is typically associated with chemotherapy only due to neuro-toxicity agents [2,22,23].
7.6.3. Nervous system effects
The clinical manifestations of neurotoxicity including: paraesthesia of the hands and feet, loss of deep tendon reflexes, weakness and rarely loss of sensation. These manifestations are mostly reversible and usually seen under chemotherapy treatment.
Studies with anti-PD-1/PD-L1 therapy have been reported in isolated cases (1%-3%) of Guillain Barre syndrome, aseptic meningitis/encephalitis and Myasthenia Gravis [2,23].
7.6.4. Pulmonary effects
The most common manifestation of pulmonary toxicity is coughing which can lead to dyspnoea and respiratory failure. Chemotherapeutic drugs can directly and indirectly damage the endothelial and epithelial cells of the lung tissue, causing pulmonary fibrosis, hypersensitivity pneumonitis and rarely acute respiratory distress syndrome.
Studies with TKI (Erlotinib, Gefitinib) therapy have been reported in isolated cases (<1%) of interstitial pneumonitis due to the inhibition of EGFR in the repair process. Antibodies against the VEGF receptor (bevacizumab) may cause haemoptysis. Therapy with anti-PD-1/PD-L1 may cause pneumonitis, either alone or in combination with other therapies, in less than 1% of patients but it may lead to death [2,23,24].
7.6.5. Hepatic effects
The clinical manifestations of hepatoxicity are highly variable, starting from asymptomatic patients to abnormal elevation of liver enzymes (AST, ALT and bilirubin) with jaundice, fever and vomiting.
Chemotherapy is the main systemic treatment cause of hepatoxicity due to direct/indirect parenchymal injury. Hepatoxicity is common (~10%) with TKI (Erlotinib, Gefitinib) therapy but rare with Bevacizumab. The incidence of hepatoxicity with anti-PD-1/PD-L1 therapy varies from 5% - 7%
[2,22,23].
7.6.6. Dermatologic effects
Dermatologic manifestations are quite common adverse reactions of systemic treatments.
Common manifestations include: dry skin, maculopapular rash, hyperpigmentation, vitiligo, pruritus, urticaria and skin appendage changes (alopecia, nail change). Some agents can cause one or multiple manifestations.
19 More than 50% of patients who receive chemotherapy may have alopecia. Most agents like Paclitaxel and Vinca alkaloids can lead to alopecia. The hair will regenerate within 2–6 months from the discontinuation of the drug. Immunotherapy and target therapy do not cause alopecia.
Hyperpigmentation can be local or diffuse. The pigmentation may involve the skin, mucosa, teeth and hair. Hyperpigmentation is associated with the chemotherapeutic agents methotrexate and bleomycin.
Skin rash and itching are common manifestations of all types of systemic treatment. The incident rate of EGFR-TKI (Erlotinib, Gefitinib) and EGFR antibodies (Cetuximab, Necitumumab) in causing skin rash is more than 45%. Due to the inhibition of EGFR which leads to the abnormal migration of keratinocyte in the skin, inflammation and papulopustular skin rash may occur. PI3K/AKT/mTOR inhibitors (Selumetinib) may cause maculopapular rash in contrast to papulopustular skin rash caused by EGFR inhibitors. The incident rate of anti-PD-1/PD-L1 mAb (Nivolumab) in causing a maculopapular rash is ~40%. In rare cases, bullous pemphigoid, Stevens- Johnson syndrome and toxic epidermal necrolysis have been reported.
Nail changes are rare and usually occur due to chemotherapeutic agents such as paclitaxel and docetaxel which can cause changes to the nail, including: subungual haemorrhage, splinter haemorrhage, Beau’s lines (transverse lines) and Mees’ lines (white, parallel lines) [2,22,23,25].
7.6.7. Cardiac effects
Chemotherapeutic agents (Cisplatin, Etoposide) can cause direct cellular injury to the myocardium, vascular injury, hypertensive effects, inflammation to the pericardium and myocardium.
These injuries can cause cardiomyopathy, pericarditis, and ECG changes.
VEGF-I (Bevacizumab) therapy has a higher risk of venous thromboembolism and cardiac ischemia. Clinical trials show a 3% risk for venous thromboembolism of all grades.
Low incidences of anti-PD-1 therapy (<1%) has been recorded related to cardiac toxicity [2,22,23].
20
8. Research Methodology and Methods
8.1. Design, patient selection and amount.
This research is a prospective study of 64 patients, who were diagnosed and confirmed histologically with stage III/IV NSCLC in the Pulmonology Department at “Kauno Klinikos” Hospital.
The study was conducted over a 3-month period (Nov. 2019- Jan. 2020). Patients were divided into 2 different groups:
Group 1: 34 patients who received different treatment regimens according to protocols. The patients were divided into 3 groups: 13 patients received chemotherapy (Cisplatin 75 mg/m2).
11 patients received immunotherapy (Atezolizumab1,200 mg/d) and 10 patients received target therapy (Gefitinib 250 mg/d). Each patient was evaluated for adverse effects after 1 cycle of therapy by an 11- item paper questionnaire derived from CTCAE version 5.0.
Group 2: 30 patients (different patients from Group 1 due to resolution of preserving the confidentiality of the patients in group 1) who received different treatment regimens: 10 patients received chemotherapy (Cisplatin 75 mg/m2). 10 patients received immunotherapy (Atezolizumab 1,200 mg/d) and 10 patients received target therapy (Gefitinib 250 mg/d).
Each patient was evaluated for anaemia after 1 cycle of therapy by lab results. Anemia is most common haematological ADR of lung cancer [2,21].
8.2. Patient questionnaire and outcome assessments.
Treatment related adverse reactions were assessed by an 11-item paper questionnaire derived from the US National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [Annex 1] and laboratory results. The 11 items were nausea, vomiting, constipation, loss of appetite, diarrhoea, fatigue, pain, dyspnoea, alopecia, headache and paraesthesia. Patients were asked to indicate if the adverse reaction occurred. If the response was “yes” then patients marked which statement best described their worst experience (grade) of that specific adverse reaction. The paper questionnaire was translated into Lithuanian. Patients filled the questionnaire at the end of the first cycle of therapy.
No assistance was provided with the filling out of the questionnaires. All patients provided written, informed agreement to their involvement in the study.
8.3. Statistical analysis
The statistical analysis was performed using “SPSS” (Statistical Package for the Social Science), version 20.0 and Microsoft Excel.Descriptive statistics were used to characterise treatment- related adverse effects. The number of adverse effects were summarised by frequencies. The independent Chi-square test was used to examine the relation between the prevalence of adverse effects in patients treated with different types of systemic drug regimens. A P < 0.05 was considered statistically significant.
21
9. Results
The research included a total of 34 participants that were grouped into three different groups according to their treatment. 13 patients were treated with chemotherapy, wherein Male=6, Female = 7.
11 patients were treated with immunotherapy, wherein Male=5,
Female =6. And 10 patients were treated with target therapy, wherein Male= 6 and Female=4.
In total, Men n=17 and women n=17. Median age was 65.1 years.
Table 1: Characterization of gender and age of participants.
Drug Gender Age group Total Percentage
less than 66
Greater than 66 Chemotherapy
Male 2 4 6 20.58%
Female 5 2 7 17.64%
7 6 13
Immunotherapy
Male 0 5 5 14.70%
Female 4 2 6 17.64%
4 7 11
Target Therapy
Male 2 4 6 17.64%
Female 3 1 4 11.76%
5 5 10
A total of 34 patient questionnaires were collected after cycle 1 of therapy. The results of the patient questionnaires are summarised and cross-tabulated in
Table 2. Questionnaires results
Drug Adverse Effect Grade Total
grades
N (%) No ADR Grade 1 Grade 2 Grade 3
Chemotherapy
(n=13) Nausea 6 (46.15) 2 (15.38) 3 (23.07) 2 (15.38)
7 (53.85)
Vomiting 10 (76.92) 2 (15.38) 0 1 (7.69) 3 (23.07)
Constipation 8 (61.53) 5 (38.46) 0 0 5 (38.46)
Loss of
appetite 4 (30.76) 4 (30.76) 4 (30.76) 1 (7.69)
9 (69.23)
Diarrhoea 10 (76.92) 3 (23.07) 0 0 3 (23.07)
Fatigue 1 (7.69) 6 (46.15) 2 (15.38) 4 (30.76) 12(92.30)
Pain 10 (76.92) 0 2 (15.38) 1 (7.69) 3 (23.07)
Dyspnoea 5 (38.46) 4 (30.76) 3 (23.07) 1 (7.69) 8 (61.53) Alopecia 1 (7.69) 6 (46.15) 6 (46.15) 0 12(92.30)
Headache 12 (92.30) 0 1 (7.69) 0 1 (7.69)
Paraesthesia 5 (38.46) 7 (53.84) 1 (7.69) 0 8 (61.53)
Total 72 39 22 10 71
Immunotherapy
(n=11) Nausea 11 (100) 0 0 0 0
Vomiting 11 (100) 0 0 0 0
Constipation 7 (63.63) 3 (27.27) 0 1 (9.09) 4 (36.36)
22
Loss of
appetite 5 (45.45) 4 (36.36) 2 (18.18) 0 6 (54.54)
Diarrhoea 5 (45.45) 6 (54.54) 0 0 6 (54.54)
Fatigue 0 10 (90.9) 0 1 (9.09) 11 (100)
Pain 1 (9.09) 8 (72.72) 2 (18.18) 0 10 (90.9)
Dyspnoea 3 (27.27) 6 (54.54) 2 (18.18) 0 8 (72.72)
Alopecia 8 (72.72) 3 (27.27) 0 0 3 (27.27)
Headache 10 (90.9) 1 (9.09) 0 0 1 (9.09)
Paraesthesia 10 (90.9) 1 (9.09) 0 0 1 (9.09)
Total 71 42 6 2 50
Target therapy
(n=10) Nausea 9 1 (10) 0 0 1 (10)
Vomiting 10 (100) 0 0 0 0
Constipation 10 (100) 0 0 0 0
Loss of
appetite 8 (80) 1 (10) 0 1 (10) 2 (20)
Diarrhoea 3 (30) 6 (60) 1 (10) 0 7 (70)
Fatigue 4 (40) 3 (30) 1 (10) 2 (20) 6 (60)
Pain 9 (90) 1 (10) 0 0 1 (10)
Dyspnoea 0 8 (80) 2 (20) 0 10 (100)
Alopecia 9 (90) 1 (10) 0 0 1 (10)
Headache 10 (100) 0 0 0 0
Paraesthesia 10 (100) 0 0 0 0
Total 82 21 4 3 28
The analysis revealed that n=28 (25.5%) cases of adverse effects were experienced after the patients were administrated target therapy. It was also revealed that n=71 (49.65%) cases of adverse effects were experienced after the patients were administered chemotherapy, Lastly, it can be seen from the analysis that n=50 (41.3%) cases of adverse reactions were recorded from patients undergoing immunotherapy.
Fatigue was the most common ADR (n=29, 85.3%) reported in the 34 patients evaluated. Loss of appetite (n=17, 50%) and dyspnoea (n=26, 76,5%) were the other frequently reported ADRs.
Headaches and vomiting was rarely reported in the 34 evaluated patients. Headache was reported by 2 patients (5.9%) and vomiting was reported by 3 patients (8.8%).
Graph 1. Describes the toxicity profile experienced by 13 patients after 1 cycle of chemotherapy. Fatigue and alopecia were the most common ADRs the patients experienced (n=12, 92.3%). Of the patients who experienced fatigue, only 33.3% were severe (grade 3: could not perform self-care tasks), while 66.6% were grade 1 & 2. Of the patients who experienced alopecia, 50% were severe (grade 2: >50% hair loss).Only 1 patient experienced headache (7.69%) after 1 cycle of chemotherapy.
23 Graph 1. Percentage of patients experienced ADR after 1 cycle of chemotherapy
Graph 2. Describes the toxicity profile experienced by 11 patients after 1 cycle of immunotherapy. All 11 patients experienced fatigue, mostly low grade (grade 1: resolved after rest).
91% of the patients experienced pain which was not present before treatment, but it was mostly low grade (grade 1: mild pain, no painkillers).
No patients experienced nausea and vomiting. Only 9% of patients experienced headache and paraesthesia.
Graph 2. Percentage of patients experienced ADR after 1 cycle of immunotherapy.
0 10 20 30 40 50 60 70 80 90 100
Nausea
Vomiting Constipation
Loss of appetite Diarrhea
Fatigue Pain
Dyspnea Alopecia
Headache Paresthesia
participants(%)
No ADR Grade 1 Grade 2 Grade 3
0 20 40 60 80 100 120
Nausea Vom
iting Cons
tipation Loss of appe
tite Diarrhea
Fatigue Pain Dyspnea
Alopecia Headache
paresthesia
participants (%)
No ADR Grade 1 Grade 2 Grade 3
24 Graph 3. Describes the toxicity profile experienced by 10 patients after 1 cycle of target therapy. All 10 patients experienced dyspnoea, mostly (80%) low grade (grade 1: dyspnoea during moderate physical effort). 70% of patients experienced diarrhoea, mostly low grade (grade 1: less than 4 evacuations per day).
No patients suffered from vomiting, constipation, headache or paraesthesia. Also, only 10% of patients experienced dyspnoea and pain which was not present before treatment.
Graph 3. Percentage of patients experienced ADR after 1 cycle of target therapy.
Table 3. Prevalence of adverse effects
Adverse effect
incidence Chemotherapy
(n=13) Immunotherapy
(n=11) Target therapy
(n=10) P value
Nausea 7 (53.85) 0 1 (10) .004
Vomiting 3 (23.07) 0 0 .070
Constipation 5 (38.46) 4 (36.36) 0 .078
Loss of appetite 9 (69.23) 6 (54.54) 2 (20) .040
Diarrhoea 3 (23.07) 6 (54.54) 7 (70) .069
Fatigue 12(92.30) 11 (100) 6 (60) .023
Pain 3 (23.07) 10 (90.9) 1 (10) .000
Dyspnoea 8 (61.53) 8 (72.72) 10 (100) .092
Alopecia 12(92.30) 3 (27.27) 1 (10) .000
Headache 1 (7.69) 1 (9.09) 0 .636
Paraesthesia 8 (61.53) 1 (9.09) 0 .001
The Chi-Square statistic test was used for testing relationships between categorical variables treatment type and adverse effect. The null hypothesis of the Chi-Square test was that there is no relationship between the treatment type and adverse effects.
It can be concluded that only the variables with a p value less than 0.05 have a significant relationship between the considered variables. It is seen that the p value of nausea (0.04), fatigue (0.023), pain (0.000), alopecia (0.000) and paraesthesia (0.001) are less than 0.05 thus, the null hypothesis is rejected.
0 20 40 60 80 100 120
Nausea
Vomiting
Constipation
Loss of appetite
Diarrhea
Fatigue Pain
Dyspnea
Alopecia
Headache
paresthesia
participants(%)
No ADR Grade 1 Grade 2 Grade 3
25 It can be concluded that treatment type had a significant effect on patients experiencing these adverse effects.
Table 4. Description of toxicity profile relative to gender.
Gender ADR Chemotherapy
N,(%) Immunotherapy
N,(%) Target Therapy
N,(%) Total
Male (n=17) Yes ADR 31 (46.96) 23 (41.8) 15 (22.72) 69 (36.9)
No ADR 35 (53.04) 32 (58.2) 51 (77.28) 108 (63.1)
Female
(n=17) Yes ADR 40 (51.94) 27 (41) 13 (29.55) 80 (42.78)
No ADR 37 (48.05) 39(59) 31 (70.45) 107 (57.2)
The study population consisted of 17 men and 17 women. The women experienced more ADR’s (42.78%)regardless of the type of therapy compared to men (36.9%). Chemotherapy was the main cause of adverse effects in both genders, while target therapy had the least adverse effects. Dyspnoea and fatigue were the most common reported ADR’s by both genders. Headache was not reported by women and vomiting was not reported by men.
The null hypothesis of the Chi-Square test was that there is no relationship between the treatment type and gender of the patients. The p value of the study with immunotherapy is 0.92, p value of the study with target therapy is 0.42 and p value of the study with chemotherapy is 0.55. All the p value are greater than 0.05, thus null hypothesis is not rejected. It can be concluded that no treatment type had a significant relationship with gender of the patient.
Graph 4. Toxicity profile relative to gender after 1 cycle
46.96 53.04 51.94 48.05
41.8
58.2
41
59
22.72
77.28
29.55
70.45
0 10 20 30 40 50 60 70 80 90
Yes ADR No ADR Yes ADR No ADR
Male Female
participants(%)
chemotherapy Immunotherapy Target Therapy
26 Graph 5. Describes the toxicity profile relative to age. 34 patients, median age 65.1 (47-78) divided into 2 age groups: age <66-year-old, age 66-year-old.
From the results of the research, patients under 66 experienced more adverse effects (44.5%) than patients over age 66 (35.85%).
Chemotherapy was the main cause of ADRs for group of age <66 year old (56.4%) while
immunotherapy was the main cause of ADRs for those in the 66 year old group (45%). Both age groups experienced the least adverse reactions from target therapy. The null hypothesis of the Chi- Square test was that there is no relationship between the treatment type and age. The p value of the study with immunotherapy is 0.94 and the p value of the study with target therapy is 0.38. null
hypothesis is not rejected. It can be concluded that immunotherapy and target therapy treatments don’t not have a relationship with age of the patient.
The p value of chemotherapy is 0.04 which is less than 0.05 thus, null hypothesis is rejected. It can be concluded that chemotherapy treatment has a significant relationship with age of the patient.
Graph 5. The toxicity profile relative to age after 1 cycle of therapy
Graph 6. Describes the anaemia profile experienced by group 2 (30 patients that are different from the patients in group 1 due to resolution of preserving the confidentiality of the patients in group 1). Anaemia was a significant adverse effect observed in patients. Anaemia was found in 17 patients (56.7%) after 1 cycle of treatment. Anaemia was most commonly observed in patients undergoing chemotherapy and immunotherapy, n=8 (80%) and n= 7 (70%) respectively.
Only 3 patients (30%) under target therapy experienced anaemia.
Grade 1 anaemia (Hb 100- 130g/L) was found in 43.4% of patients, Grade 2 anaemia (80-100g/L) was found in 13.4% of patients and no incidence of Grade 3 (<80g/L) was found.
The null hypothesis of the Chi-Square test was that there is no relationship between the treatment type and anemia adverse effect. The p value of the study with target therapy is 0.11, null hypothesis is not
56.42
23.08 20.52
44.58
33 26.8
40.2
55.42
38.03
45.07
17
35.85
30.7 35.44 33.9
64.14
0 10 20 30 40 50 60 70
chemotherapy immunotherapy target therapy total
participants (%)
age <66 yes ADR age <66 no ADR age ≥66 yes ADR age ≥66 no ADR
27 rejected. It can be concluded that target therapy had no significant relationship with anemia adverse effect. The p value of the study with chemotherapy is 0.03 and the p value of the study with immunotherapy is 0.01, both less than 0.05 thus, null hypothesis is rejected. It can be concluded that chemotherapy and immunotherapy treatments have a significant relationship with anemia adverse effect.
Graph 6. Patients experiencing various grade of anemia after 1 cycle of therapy
0 10 20 30 40 50 60 70 80 90
No Anemia Grade 1 Grade 2 Grade 3
participants(%)
Chemotherapy Immunotherapy Target therapy
28
10. Discussion
The aim of the research was to analyse and compare the adverse reactions of different systemic lung cancer treatments in patients with lung cancer in the Pulmonology Department of “Kauno Klinikos”
hospital, Lithuania.
Between Nov.2019 -Jan.2020, 34 patients were evaluated for ADRs after undergoing 1 cycle of therapy. The research revealed that 49.65% patients undergoing chemotherapy experienced ADRs.
While in patients undergoing target therapy ADRs were only experienced by 25.5% of patients. Among the 34 patients, fatigue was the most common adverse effect (n=29, 85.3%) reported. Headache and vomiting was rarely reported among the 34 patients. Headache was reported by 2 patients (5.9%) and vomiting was reported by 3 patients (8.8%). The variation of toxicity profile encountered during therapy depends on several factors (therapy protocols, dose and genetic predisposition to various adverse effects) that may explain such difference.
Statistically, no relation was found between treatment type and some of the adverse effects (nausea, fatigue, pain, alopecia and paraesthesia).
Anaemia was a significant problem observed in the research. At end of first cycle of therapy, grade 1 anaemia was most commonly observed in patients undergoing chemotherapy and immunotherapy. Also, grade 1 anaemia was commonly observed in a study from India of 112 patients undergoing 1 chemotherapy cycle (Singla R et al. [27]), grade 1 anaemia was found in 25% patients and grade 2 in 15% patients, grade 3 less than 5%. Anaemia is a considerable cause for restraining or discontinuation of the therapy. Although the aetiology of anaemia wasn’t determined, comorbidities and nutritional deficiency may play a major role.
During the research, the incidence and severity of ADRs were higher in women but statistically no relation was found between treatment type and gender. Chemotherapy was the main cause of ADRs in both genders, while target therapy was the least probable to cause ADRs. Özdemir BC et al. [26]
explains why women are more susceptible to toxicity. Women have higher body fat and plasma volume which affects pharmacokinetics, especially the distribution of agent. Also, some pharmacokinetic analysis explained that men have a higher elimination rate and capacity of different anticancer agents.
In the results of this study reflected that younger patients (age <66 year old) were more likely to experience side effects, especially by chemotherapy. These results are incompatible with the results of studies performed in Turkey and USA Tas F, Ramalingam S et al. [28,29]. In their studies, the elderly (age>70 years) experienced most of the ADRs. The results of these studies suggest that by giving lower dose of treatment to older patients, risk for ADRs may be reduced.
There are several limitations in this study. Firstly, data collection of toxicity occurred after 1 cycle of therapy, so long- term toxicities could not be assessed. Secondly, the actual dose of drug given
29 to individual patient was not recorded. This study leans on standard doses for each drug, but the dose might have been adjusted by the physician according to the patient’s medical condition.
In conclusion, the primary goal of systemic therapy is to extend survival. Chemotherapy is still the primary treatment for NSCLC, although most of patients experienced ADRs under this therapy.
Target therapy showed the lowest rate of ADRs among patients.
Treatment benefits to increase survival need to weighed against the treatment-associated toxicities.
11. Conclusions
1. Systemic assessment including questionnaires are a key factor in improving data collection regarding side effects from patients. This information might be lost due to poor communication between physicians and patients or some physicians are less likely to ask about unexpected toxicities.
2. By using descriptive analysis, it was found that chemotherapy is more likely to cause adverse effects during treatment of NSCLC.
3. The adverse toxicities: nausea, fatigue, pain, alopecia and paraesthesia may occur in all types of systemic treatment of NSCLC and are not related to specific treatment.
4. It can be concluded that target therapy yields a favourable toxicity profile. It suggests that target therapy may be a safe treatment approach in patients with NSCLC.
30
References
1. Huang CY, Ju DT, Chang CF, Muralidhar Reddy P, Velmurugan BK. A review on the effects of current chemotherapy drugs and natural agents in treating non-small cell lung cancer. Biomed.
2017;7(4):12–23.
2. Remesh A. Toxicities of anticancer drugs and its management. Int J Basic Clin Pharmacol.
2012;1(1):2.
3. Zheng M. 4.pdf. Surg Oncol Clin N Am [Internet]. 2016;25(3):447–68. Available from:
https://cbc.org.br/wp-content/uploads/2016/07/072016SCOc.pdf
4. Das C, Lucia MS HK and TJ. 乳鼠心肌提取 HHS Public Access. Physiol Behav.
2017;176(3):139–48.
5. Travis WD. Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other non-small cell carcinomas. Mod Pathol. 2012;25:18–30.
6. Zappa C, Mousa SA. Non-small cell lung cancer: Current treatment and future advances. Transl Lung Cancer Res. 2016;5(3):288–300.
7. Manuscript A. Rural greening and community development programme , Shri AMM
Murugappa Chettiar research c1. Manuscript A. Rural greening and community development programme , Shri AMM Murugappa Chettiar research centre , Chennai . 2013;32(4):11. entre , Chennai . 2013;32(4):11.
8. Akhtar N, Bansal JG. Risk factors of Lung Cancer in nonsmoker. Curr Probl Cancer [Internet].
2017;41(5):328–39. Available from: http://dx.doi.org/10.1016/j.currproblcancer.2017.07.002 9. Latimer KM, Mott TF, Pensacola NH. Lung Cancer: Diagnosis, Treatment Principles, and
Screening. 2015;
10. Hammerschmidt S, Wirtz H. Lungenkarzinom - Aktuelle diagnostik und therapie. Dtsch Arztebl. 2009;106(49):809–20.
11. Spiro SG, Gould MK, Colice GL. Initial evaluation of the patient with lung cancer: Symptoms, signs, laboratory tests, and paraneoplastic syndromes. ACCP evidenced-based clinical practice guidelines (2nd edition). Chest. 2007;132(3 SUPPL.):149S-160S.
12. Detterbeck FC. The eighth edition TNM stage classification for lung cancer: What does it mean on main street? J Thorac Cardiovasc Surg [Internet]. 2018;155(1):356–9. Available from:
https://doi.org/10.1016/j.jtcvs.2017.08.138
13. Pirker R. Milestones in the systemic treatment of lung cancer. Memo - Mag Eur Med Oncol.
2017;10(1):22–6.
14. Tiefenbacher A, Pirker R. Systemic treatment of advanced non-small cell lung cancer:
controversies and perspectives. Memo - Mag Eur Med Oncol. 2018;11(2):112–5.
31 15. Lash BW, Gilman PB. Principles of Cytotoxic Chemotherapy. Cancer Immunother Immune
Suppr Tumor Growth Second Ed. 2013;167–85.
16. Dickens E, Ahmed S. Principles of cancer treatment by chemotherapy. Surg (United Kingdom) [Internet]. 2018;36(3):134–8. Available from: https://doi.org/10.1016/j.mpsur.2017.12.002 17. Chirieac LR, Dacic S. Targeted therapies in lung cancer. Surg Pathol Clin. 2010;3(1):71–82.
18. Chan BA, Hughes BGM. Targeted therapy for non-small cell lung cancer: Current standards and the promise of the future. Transl Lung Cancer Res. 2015;4(1):36–54.
19. Cortinovis D, Abbate M, Bidoli P, Capici S, Canova S. Targeted therapies and immunotherapy in non-small-cell lung cancer. Ecancermedicalscience. 2016;10:1–28.
20. Kanwal B, Biswas S, Seminara RS, Jeet C. Immunotherapy in Advanced Non-small Cell Lung Cancer Patients: Ushering Chemotherapy Through the Checkpoint Inhibitors? Cureus.
2018;10(9).
21. Singla R, Mallick M, Mrigpuri P, Singla N, Gupta A. Intrathoracic liposarcoma : Case report with emphasis to histogenesis and site of origin classification problems Tracheoesophageal fistula diagnosis during open tracheostomy. 2018;35(2):2017–9.
22. Liu S, Kurzrock R. Toxicity of targeted therapy: Implications for response and impact of genetic polymorphisms. Cancer Treat Rev [Internet]. 2014;40(7):883–91. Available from:
http://dx.doi.org/10.1016/j.ctrv.2014.05.003 23. Daniel Y. Wang DBJ. 34.pdf. 2018.
24. Charpidou AG, Gkiozos I, Tsimpoukis S, Apostolaki D, Dilana KD, Karapanagiotou EM, et al.
Therapy-induced toxicity of the lungs: An overview. Anticancer Res. 2009;29(2):631–9.
25. Ding L, Li QJ, Wang Y, Bi ZF, Chai J, Jiang ZM, et al. Specific skin changes induced by chemotherapy. Transl Cancer Res. 2018;7(3):E5–13.
26. Özdemir BC, Csajka C, Dotto GP, Wagner AD. Sex differences in efficacy and toxicity of systemic treatments: An undervalued issue in the era of precision oncology. J Clin Oncol.
2018;36(26):2680–3.
27. Singla R, Mallick M, Mrigpuri P, Singla N, Gupta A. Intrathoracic liposarcoma : Case report with emphasis to histogenesis and site of origin classification problems Tracheoesophageal fistula diagnosis during open tracheostomy. 2018;35(2):2017–9.
28. Tas F, Ciftci R, Kilic L, Karabulut S. Age is a prognostic factor affecting survival in lung cancer patients. Oncol Lett. 2013;6(5):1507–13.
29. Ramalingam S, Barstis J, Perry MC, La Rocca R V., Nattam SR, Rinaldi D, et al. Treatment of elderly non-small cell lung cancer patients with three different schedules of weekly paclitaxel in combination with carboplatin: Subanalysis of a randomized trial. J Thorac Oncol [Internet].
2006;1(3):240–4. Available from: http://dx.doi.org/10.1016/S1556-0864(15)31574-
32 Annex 1.
This questionnaire is about adverse reactions during the course of your treatment. please answer all of the questions yourself by marking the option that best applies to you. There are no “right” or “wrong”
answers.
The information that you provide will remain strictly confidential.
Male / female
Your birthdate (month, year) _____________________
1. Have you felt nausea? NO if no, go to item 2
YES if yes, chose one of the definitions below G1. I felt nausea, but I was able to eat and drink as usual.
G2 I felt nausea, and because of that I ate and drink less than usual.
G3 because of nausea I wasn’t able to eat and drink for several days. For this reason, I was given intravenous fluid and/or artificial nutrition.
2. Have you vomited? NO if no, go to item 3
YES if yes, chose one of the definitions below G1. I vomited multiple times a day, but no intervention/treatment was needed.
G2 I vomited multiple times a day and outpatient IV hydration was needed.
G3 because of vomiting, hospitalization was needed and I was given IV hydration And/or artificial nutrition.
G4 because of vomiting, I felt my life was in danger and I needed urgent hospitalization
3. Have you experienced difficulty with evacuation?
NO if no, go to item 4
YES if yes, chose one of the definitions below G1. I have sometimes experienced some difficulty with evacuation, but these resolved modifying my dietary habits and/or by occasionally taking laxatives or using enema
G2 Persistent difficulty with evacuation while regular use of laxatives or enemas G3 Because of difficulty with evacuation, I needed manual evacuation
G4 Because of difficulty with evacuation, I felt my life was in danger and I needed urgent hospitalization
33 4. Have you experienced loss of appetite?
NO if no, go to item 5
YES if yes, chose one of the definitions below
G1 I had some loss of appetite, but I ate and drank as usual
G2 I had some loss of appetite that cause reduction in eating and drinking, but I did not lose much weight
G3 I had serious loss of appetite, which caused significant weight loss
G4 Because of severe loss of appetite, I was given intravenous fluids and/or nutrients
5. Have you had diarrhea?
NO if no, go to item 6
YES if yes, chose one of the definitions below G1 I had less than 4 more evacuations beyond usual per day
G2 I had 4-6 more evacuations beyond usual per day G3 I had 7 of more evacuations beyond usual per day
G4 Because of diarrhea, I needed urgent hospitalization and I felt that my life was in danger.
6. Have you felt tired?
NO if no, go to item 7
YES if yes, chose one of the definitions below G1 I had felt tired, sometimes, but it resolved completely or almost completely after rest G2 I felt tired that was not relieved by rest
G3 I felt very tired and because of tiredness I was barely able or not able at all to perform self-care task (i.e. getting dressed, having a shower...)
