Monday, April 1, 2024

Lung Cancer: Conventional Treatment and Other Integrated Therapeutic Modalities

 

Lung cancer is one of the major causes of death.  It is the 2nd most common cancer worldwide, more common in men and the 2nd most common cancer in women.

There were more than 2.5 million new cases of lung cancer in 2020.

In Malaysia lung cancer accounts for approximately 10.6 % out of a total of 48,639 of all malignancies in 2020. The most common cancers in Malaysia in 2020 are: breast (17.3 %) colorectal (13.6 %), lung (10.6 %), nasopharyngeal (4.6 %), liver (4.4 %) and others (48.6 %)

 The lifetime risk is approximately 1 in 55 for Malaysian males. The risk is highest in Chinese males (1 in 43), followed by Malays (1 in 62) and Indians (1 in 103). For women, the risk is approximately 1 in 135, although in recent years the incidence of lung cancer has shown an increase in women even though females are less likely to smoke compared to males. The age-standardized incidence rate of lung cancer increases rapidly from age 45 years and is highest in the 60- to 74-year-old age group. Nearly 90% of lung cancer patients in Malaysia are diagnosed with stage III or IV disease. 

 

Pathophysiology:

 

The classical bifurcation of lung cancer is non-small cell lung cancer (NSCLC), the more common type, and small cell lung cancer (SCLC). SCLC is typically less amenable to surgical resection, whereas NSCLC can more often be treated with surgery. NSCLC can be divided into three major histological subtypes, namely, squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. It is also possible for lung cancers that have mixed features to be identified as mixed small cell and large cell cancer.

 

Signs and Symptoms:

 

Symptoms do not normally occur until the cancer is advanced and can include persistent cough, haemoptysis, chest pain, voice change, example hoarseness, worsening shortness of breath, recurrent pneumonia, or bronchitis. 

 

Risk Factors:

 

Smoking and Tobacco Use:

 

Cigarette smoking is by far the most important risk factor for lung cancer, wherein risk increases with both the quantity and duration of smoking.1 Approximately 90 % of lung cancers are the result of tobacco use, and the risk of a smoker developing lung cancer is 25 times greater than that of a non-smoker. Smoking is strongly linked with SCLC and squamous cell carcinoma, and adenocarcinoma is the most common type in patients who have never smoked.3 

 

Environmental Carcinogen:

 

Environmental risk factors that have been implicated in lung cancer includes exposure to radon as the second most common cause, second-hand smoke, asbestos, metals like chromium and cadmium, tar exposure, arsenic, certain organic chemicals such as bis(chloromethyl) ether, silica, radiation exposure, air pollution, and diesel exhaust. Certain occupations may increase exposure to lung carcinogens, including rubber manufacturing, paving, painting, and chimney sweeping in cold countries. In addition to asbestos exposure, cigarette smoking greatly increases the chances of an asbestos-related lung cancer. 

 

Genetic and Biomarkers:

 

Lung cancer is a complex and heterogeneous disease, not only at the biochemical level involving genes, protein, metabolites, but also at the tissue, organism, and population level.There are many early detection biomarkers for lung cancer, including both tissue and biofluid-based biomarkers such as airway epithelium, sputum, blood, and exhaled breath. Mutation in p53 has been seen in chronic smokers before there is evidence of neoplasia, making it a potentially useful predictor of lung cancer. Due to the heterogeneity of lung cancer, detection by one single biomarker remains difficult. Panels of biomarkers can be useful, but these frequently have overlap with other diseases, especially other cancers and inflammatory conditions. 5

 

Screening and Detection: 

 

Compared with standard chest X-ray (CXR), screening with spiral computed tomography (CT) has been shown to reduce lung cancer-related deaths by 16-20 % among adults with a 30 pack-year history who were current smokers or who had quit within the past 15 years. Current American Cancer Society guidelines suggest discussing utilization of low dose helical CT (LDCT) in current or former smokers aged 55 - 74 years in good health with at least a 30 pack-year history of smoking. A "pack-year " is the packs of cigarettes smoked a day (1 pack = 20 cigarettes) multiplied by the number of years smoked. "Clinicians with access to high-volume, high -quality lung cancer screening and treatment centres should initiate a discussion about lung cancer screening with apparently healthy patients ages 55-74 who have at least a 30 pack-year smoking history and who currently smoke or have quit within the past 15 years. A process of informed and shared decision making with a clinician related to the potential benefit, limitations, and harms associated with screening for lung cancer with LDCT should occur before any decision is made to initiate lung cancer screening. Smoking cessation counselling remains a high priority for clinical attention in discussions with current smokers, who should be informed of their continuing risk for lung cancer. Screening should be viewed as an alternative to smoking cessation.

 

Low-dose helical CT (LDCT) is recommended annually starting at age of 55 till 79 in those with a 30 pack-year smoking history. This recommendation continues if a nodule measuring </- 4 mm is found. For nodules that measure 4-6 mm repeat LDCT in 6 months. If the nodule grows to 6 -8 mm or greater, radiology may recommend positron emission tomography (PET) / CT or bronchoscopy based on nodule characteristics.

 

Chest Radiography: 

 

CXR is no longer recommended as the screening technique for lung cancer and is less useful than newer technologies such as LDCT. According to the large Prostate, Lung, Colorectal, and Ovarian cancer screening trial published in 2011, annual screening with chest radiography did not reduce lung cancer mortality when compared with a "usual care" group who did not receive an annual chest radiography.7

 

Sputum Cytology:

 

This technique is more likely to be helpful in the detection of cancer that start in the major airways, such as squamous cell lung cancer.8 According to four prospective randomized controlled studies of lung cancer screening using a combination of CXR and sputum cytology there is no significant reduction in lung cancer mortality associated with an invitation to undergo sputum cytology screening. 

 

Positron Emission Tomography (PET):

 

Not all patients with lung cancer will require a PET scan; however, it can be a useful tool for determining cancer staging.9 It can be effective for determining the level of tissue activity and is more effective than CT in distinguishing between benign and malignant lesion. 10 Glucose uptake alone is nonspecific because it can be increased with inflammatory conditions.

 

Laser Bronchoscopy:

 

Conventional white-light bronchoscopy (WLB) alone identifies the lesion in only 29 % of cases. 11

 

Conventional Treatment: 

 

Conventional treatment includes surgery, radiofrequency ablation (RFA), radiation therapy, chemotherapies, targeted therapies, and immunotherapy. Palliative therapies may also be used to help with symptoms. 

 

Surgery:

 

Surgery to remove lung cancer may be an option for early-stage NSCLC. More advanced lung cancer, especially with metastasis, may not be helpful by surgery. If surgery can be done early, it provides the best chance to cure NSCLC. The risk for serious consequences is high 8 Types of lung surgery includes pneumonectomy, lobectomy, and segmentectomy (wedge resection). 

 

Radiofrequency Ablation:

 

RFA may be useful for some small cell NSCLC tumours that are near the edge of the lungs, especially in people who cannot tolerate surgery. In RFA, a thin probe is used to heat the tumour to destroy the cancer cells. This is typically done as an outpatient procedure. Major complications are uncommon but can include a partial collapse of the lungs or bleeding into the lungs. 8        

 

Chemotherapy:

 

Patients with SCLC are frequently treated with chemotherapy. If the disease is in a limited stage, radiation therapy and rarely surgery may be used for SCLC. 20 The side effects of treatment with chemotherapy for SCLC include hair loss, mouth scores, loss of appetite, nausea, vomiting, diarrhoea, constipation, immunodeficiency such as myelosuppression (decreased blood cell counts).

   easy bruising, and fatigue 

 

The list of chemo drugs used are:  

 

  1. Platinum-Based Chemotherapy:
    • Cisplatin
    • Carboplatin
  2. Paclitaxel and Docetaxel:
    • Paclitaxel
    • Docetaxel
  3. Vinorelbine
  4. Gemcitabine
  5. Epidermal Growth Factor Receptor (EGFR) Inhibitors:
    • Erlotinib
    • Gefitinib
    • Afatinib
    • Osimertinib (for patients with EGFR mutations)
  6. Anaplastic Lymphoma Kinase (ALK) Inhibitors:
    • Crizotinib
    • Ceritinib
    • Alectinib
    • Lorlatinib
  7. Programmed Death-Ligand 1 (PD-L1) Inhibitors:
    • Pembrolizumab
    • Atezolizumab
    • Durvalumab
    • Nivolumab
  8. Tyrosine Kinase Inhibitors (TKIs):
    • Bevacizumab (targets vascular endothelial growth factor, VEGF)

Side effects of these drugs can vary, and not everyone will experience the same side effects. Common side effects may include fatigue, nausea and vomiting (antiemetic) diarrhoea, hair loss, and myelosuppression (decreased blood cell counts).

 

Radiation Therapy: 

 

The two major types of radiation therapy include external beam radiation therapy (EBRT) and brachytherapy, a type of internal radiation therapy. The use of EBRT is less common than in the past because there are newer treatments that allow for greater accuracy. When radiation is given with chemotherapy, the side effects are often worse. 

 

Fever therapy or pyrotherapy (artificial fever):

Induced fever is another method of treatment by raising the body temperature or sustaining an elevated body temperature using a fever. In general, the body temperature was maintained at 41 ° C (105 ° F). Many diseases were treated by this method in the first half of the 20th century. In general, it was done by exposing the patient to hot baths, warm air, or (electric) blankets. The technique reached its peak of sophistication in the early 20th century with malariotherapy, in which Plasmodium vivax, a causative agent of malaria, was allowed to infect already ill patients in order to produce intense fever for therapeutic ends. The sophistication of this approach lay in using effective anti-malarial drugs to control the P. vivax infection, while maintaining the fever it causes to the detriment of other, ongoing, and then-incurable infections present in the patient, such as late-stage syphilis. This type of pyrotherapy was most famously used by psychiatrist Julius Wagner-Jauregg, who won the Nobel Prize for Medicine in 1927 for his elaboration of the procedure in treating neurosyphilis. However, this method of using malarial parasite to induce a fever is no longer used but is replaced by the term ‘hyperthermia therapy’ today which is essentially the same thing serving the same purpose of elevating the body temperature to levels higher than normal (typically around 41-45° C) using external methods such as heat blankets, warm water immersion, or focused microwave or radiofrequency energy. Today fever therapy is used as a treatment for cancer because high temperatures can damage and kill cancer cells.

It's commonly used in cancer treatment as a complementary therapy alongside other treatments like chemotherapy or radiation therapy. The elevated temperature can help in several ways:

  1. Direct Cell Damage: High temperatures can directly damage and kill cancer cells.
  2. Sensitizing Effect: Hyperthermia can make cancer cells more sensitive to radiation or chemotherapy, enhancing the effectiveness of these treatments.
  3. Immune System Stimulation: It may also stimulate the body's immune response, aiding in the destruction of cancer cells.

Overall, hyperthermia treatment can be effective in certain cases of cancer treatment, especially when combined with other therapies. However, its effectiveness varies depending on factors such as the type and stage of cancer, as well as individual patient factors. It's often used as part of a comprehensive treatment plan tailored to each patient's specific needs.

Alternative Therapies to Consider:

Research is ongoing at various stages with herbal and natural preparations with astragalus, ginseng, pomegranate, rosemary, sage, parsley, oregano, and various combinations of Chinese herbs, although conclusive evidence may not be apparent yet. Another potential anti-cancer herb is Sabah snake grass (Clinacanthus nutans) and lemon grass or serai, in the Malay language. See some of the many scientific papers published on the use of lemon grass for the treatment of cancers here: 

   https://www.scielo.br/j/cta/a/YwZrtspBFZZMFxrPrMK9Lvs/?format=pdf&lang=en#:~:text=Lemongrass%20extract%20possesses%20potent%20anticancer,Cancer%20Therapies%2C%2018%2C%201534735419889150.

https://www.thenaturalhealthmarket.co.uk/blog/lemongrass-tea-kills-cancer-cells-fact-or-fantastical-thinking/

https://www.researchgate.net/publication/265842609_Anticancer_effect_of_lemongrass_oil_and_citral_on_cervical_cancer_cell_lines

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918039/

https://www.nature.com/articles/nindia.2014.45

https://www.sciencedirect.com/science/article/abs/pii/S1773224723000357

Here is just one research paper among several dozen published on the use of Clinacanthus nutans (Sabah snake grass) for treating cancers. https://www.hindawi.com/journals/ecam/2021/5560502/

Patients with lung cancer and other poor-outlook cancers are particularly vulnerable to heavily promoted claims for unproven or disproven "alternatives". Inquiring about the patients' uses of these therapies should be routine because these practices may be harmful and can delay or impair treatment. However, physician-guided mind-body modalities and massage therapy can reduce anxiety, mood disturbances, and chronic pain. Acupuncture can assist in the control of pain and other side effects and help reduce quantities of pain medication that may be required. 

Yoga:

Some controlled trials suggest yoga is beneficial for chemotherapy-induced nausea, anticipatory nausea, pain, invigoration, acceptance, fatigue, and appetite loss, and can decrease salivary cortisol levels. Investigators also report a positive dose-response relationship. 

Massage:

Massage therapy, an effective adjunct to cancer supportive care, can reduce anxiety, depression, and pain. The evidence that supports its effect on anxiety is stronger than that on depression. 

Exercise-Based Pulmonary Rehabilitation:

Overall, the studies published to date suggest that short-term (6 - 8 weeks), low-intensity, multidisciplinary, exercise-based rehabilitation is potentially feasible and safe for select patients with inoperable NSCLC. The preliminary data further suggest that low-intensity, multidisciplinary, exercise-based rehabilitation is associated with modest improvements in exercise tolerance and functional capacity endpoints in select patients who are able to tolerate and achieve reasonable adherence.

Acupuncture:

Acupuncture is a relatively safe and minimally invasive modality that may be useful for treating symptoms of lung cancer and side effects of anticancer treatment. A small case series showed some improvement in both an analogue pain scale and well-being score for patients with lung cancer. Overall, there is a lack of data on whether acupuncture could be useful in the treatment of chemotherapy-induced peripheral neuropathy. 

 

Nutrition: 

Nausea and vomiting are common side effects of chemotherapy treatments. There are numerous methods for treating chemotherapy-related nausea, including corticosteroids, dopamine antagonists, serotonin antagonists, benzodiazepines, aprepitant, and cannabinoids. One of the best natural medicines for nausea is ginger. Ginger can also be recommended for both its anti-nausea and anti-cancer benefits 15 Generally a diet rich in non-starchy vegetables and fruits and low in red meat is recommended B-complex vitamins, tea, and cruciferous vegetables can also be recommended. For patients with weight loss, nutritional supplements may be recommended along with a diet rich in protein while still limiting red meat consumption. In patients with sarcopenia, supplementation with n-3 fatty acids may be beneficial.13 Oral supplementation of eicosapentaenoic acid (EPA) in patients with NSCLC significantly improves energy, protein intake, and body composition, while decreasing fatigue, neuropathy, loss of appetite, according to a randomized trial. 16

Curcumin is a food and herbal medicine, scientifically called diferuloylmethane. It is a hydrophobic polyphenol that is the main curcuminoid of turmeric. "The mechanism implicated as a good natural anticancer medicine in the inhibition of tumour genesis by curcumin are diverse and appear to involve a combination of anti-inflammatory, antioxidant, immunomodulatory, proapoptotic, and anti-angiogenic properties via pleiotropic effects on genes and signalling pathways at multiple levels. 17 Gene inhibition of cyclooxygenase (COX)-2 is thought to be the main anti-inflammatory activity of curcumin. Curcumin tends to be well tolerated, however, its systemic bioavailability after dosing is poor, which may limit its effectiveness outside the gastrointestinal tract. However, pipevine, a major component of black pepper, has been shown to increase the bioavailability of curcumin.18 

Prevention:

Smoking cessation continues to be the most important factor in reducing the risk for lung cancer. People who discontinue smoking, even well into middle age, avoid most of the subsequent risk for lung cancer, and discontinue smoking before middle age avoids more than 90 % of the risk attributable toobacco.19

However, in recent years women who hardly smoke unlike men are also found to develop lung cancer for reasons unknown to medical scientists. 

 


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