The doctors and related professionals have evaluated the diagnosis of non-small cell lung cancer. They have recommended the best treatment approach and care for the patients. Hence, the team responsible for this is a multidisciplinary team (MDT). Treatment options depend on few things like the location of cancer occurrence, its extent of spreading while estimating the stage. And also the abnormalities of the cells when observed under the microscope, and general health of the patients. The treatment options for the patients for non-small cell lung cancer are:
The patients suffering from stage I, II, and IIIA NSCLC have undergone surgeries to remove the tumor. Additionally, doctors do it if the tumor is ampullary and the patient shows a high tolerance level towards surgery. The surgeons are also responsible for removing the lobe or section consisting of the tumor from the lungs. Imaging studies and biopsies help determine metastasis. And we also integrate the operability for determining the evaluation of the patient’s factors. Many surgeons are utilizing video-assisted thoracoscopy surgery (VATS). In this method they make a small incision within the chest region and insert a thoracoscopy. They remove the lobe through the scope with a small incision so that there’s no need for larger incisions 1. Some of the most common surgeries are:
This surgical procedure includes an appropriate assessment of respectability, cardiopulmonary reserve, and perioperative risk. The use of high-resolution computed tomography (CT) and positron emission tomography (PET) scanning has also been effective for preoperative planning in early-stage lung cancer. In this surgical process, the NSCLC patients are given preoperative forced expiratory volume in one second (FEV1) of greater than 2.5 L to tolerate a pneumonectomy. Lobectomy is possible with FEV1 of 1.1-2.4 L. Doctors don’t recommend surgery for NSCLC patients having FEV1 of less than 1 L. Mainly these factors change by the presence of cardiac disease or other comorbid conditions.
Lobectomy and pneumonectomy
Lobectomy is the most standard surgical approach that helps preserve pulmonary function while allowing appropriate resection. The proximal tumors require extensive pneumonectomy surgical processes that mainly consist of significant operative mortality and also long-term morbidity. Hence, in such NSCLC patients, one can consider surgical approaches such as sleeve resection.
This surgical process is generally for patients with a poor pulmonary reserve. Doctors mainly do it along with video-assisted thoracoscopy surgery (VATS).
Video-assisted thoracoscopic surgery
It is a minimally invasive surgical modality for both diagnostic and therapeutic lung cancer surgery. It mainly provides low perioperative morbidity and mortality, pain reduction, and related hospitalization. The recurrence rate and prolonged survival have shown similarity with the traditional open thoracotomies. The older age group mainly tolerates this treatment of surgical processes. The patients undergoing VATS tend to show fewer delays and reduced dosage in case of adjuvant chemotherapy.
It should involve the exploration and removal of lymph nodes from stations 2R, 4R, 7, 8, and 9 for right-side cancers and stations 4L, 5, 6, 7, 8, and 9 for left-side cancers.
NSCLC patients have undergone resection surgery that shows advantages of performing adjuvant therapy towards risk reduction of lung cancer relapse. The adjuvant treatment also includes radiation, chemotherapy, and targeted therapy. The NSCLC patients diagnosed with stage IIA, IIB, and IIIA have undergone chemotherapy. Doctors do this after the surgery for killing the remaining tumor cells for prolonged survival.
Around 40% of newly diagnosed NSCLC patients are of stage IV diagnosis. The primary aim of treating such patients is to improve their survival rate and minimize the adverse events related to the disease. The integration of cytotoxic combination chemotherapy is the first-line therapy given to the stage IV NSCLC patients being influenced by age, histology, comorbidities, and performance status (PS) 2. As per the study of the American Society of Clinical Oncology, it is revealed that the NSCLC patients of stage 0 and stage 1 are treated with platinum (cisplatin or carboplatin) in a combination of paclitaxel, gemcitabine, docetaxel, vinorelbine, irinotecan, or pemetrexed 3.
Clinical Trials and Research
Multi-center randomized clinical trials have been carried out using the above agents, revealing platinum or carboplatin to show similar results. Approximately median overall survival rates have been observed among the NSCLC patients for about 8–10 months 4–7. The particular combination type entirely depends upon its type and frequencies of toxic effects and needs to be supplemented as per the individual’s requirement. The NSCLC patients suffering from adenocarcinoma show beneficial effects from pemetrexed. The use of cisplatin is more effective than platinum but still offers more side effects. The NSCLC patients showing performance status (PS) 2 reveals that the patients may require only one drug, which is not the typical form of platinum 8.
Therefore, during the chemotherapy treatment, the major adverse events must change the chemotherapy agents. Also, the therapy must stop if cancer grows or the disease is stable after giving four treatments, but the treatment does not eliminate or reduce the tumor size 9,10. The NSCLC patients with PS evaluated as three do not show any beneficial effects from adhering to cytotoxic chemotherapy as even worse conditions may occur due to the high risk of adverse events that may further affect the patients’ quality of life. Hence, such patients majorly require supportive care as per the doctors’ recommendations. Doctors give some of the common drugs during the chemotherapy for treating lung cancer, including a mixture of 2-3 drugs altogether or a single pill at a time. Carboplatin, Cisplatin, Docetaxel, Etoposide, Gemcitabine, Nab-paclitaxel, Paclitaxel, Pemetrexed, and Vinorelbine are the standard drugs.
This treatment aims to utilize high-energy beams to damage the DNA within the cancer cells and later destroy them. This treatment can control and eliminate the tumors at the specific site within the body. NSCLC patients who have tumors detected within the chest region and who cannot undergo surgical resection benefit from the radiotherapy treatment. Radiotherapy is also considered a palliative care intervention that aims to improve the quality of life of NSCLC patients who are not responding to surgery and chemotherapy 11.
Doctors recommend another primary technique of radiotherapy treatment is known as stereotactic body radiation therapy (SBRT). It is used among the NSCLC patients diagnosed with early-stage NSCLC cancer and majorly have single small nodules within the lungs without showing any metastasis towards the nearby lymph nodes. This technique utilizes an advanced coordinate system for accurately locating the site of tumor formation and offering adequate placement of the tracking device. It results in delivering the most concentrated and highly focused radiation treatment.
The NSCLC patients have improved survival rate by adhering to the personalized medicine that aims for targeting the actual molecular targets in tumors 12. The presence of some of the targeted agents has been studied, which have shown successful integration against epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements. The analysis of molecular changes has been found through genomic testing, mainly involving the gene rearrangements of ROS1 and RET, amplification of MET and activating mutations in BRAF, HER2 and KRAS genes that may be considered as the key targets for future therapies.
Epidermal growth factor receptor (EGFR) gene
The type of cell-surface tyrosine kinase receptor contributes to activating the pathways concerned with the growth of cells and their proliferation during its activation. The mutation of the EGFR gene evolves uncontrolled cell division by constant activation in cancer. Approximately 10–15% of adenocarcinomas patients of lung cancer who belong to European and Asian descent and who never smoked along with female patients have been observed with EGFR gene mutations 13–15.
The characteristics mentioned above are predominant among the NSCLC patients while evolving the use of mutation testing, which is considered fundamental in choosing such patients who benefit from the targeted tyrosine kinase inhibitor therapy. In this treatment approach, the exon numbers ranging from 18-21 have shown mutational changes to the EGFR gene, showing sensitivity to EGFR tyrosine kinase inhibitors. Also, these exons are responsible for encoding a part of the EGFR kinase domain.
It is mainly known to be an oncogene that shows mutations related to NSCLC occurring due to the missense mutations that exchange the position of the amino acid at 12, 13 or 61. Identifying predominant single amino acid mutations has been observed at residues G12 and G13. Identifying KRAS mutations is common among adenocarcinoma patients, Caucasians, and individuals with a smoking history 16. Around 10–25% of the adenocarcinoma patients have been observed with KRAS mutation-associated tumors 17. The presence of KRAS has been observed within different tumor types, which are wild types such as EGFR and ALK, representing mutations of the new molecular subset of NSCLC. The prognostic value of KRAS mutations is possible as the available data shows limitations as the sole predictor for EGFR tyrosine kinase inhibitors or cytotoxic chemotherapy.
Anaplastic lymphoma kinase (ALK)
The previous studies have revealed that almost 3-7% of all lung tumors consist of ALK mutations, mainly observed among the NSCLC patients of the younger age group showing modifications 18,19. The adenocarcinoma patients with acinar histology or signet ring cells or those who have never smoked show ALK mutations 20,21. Rearrangement in EML-4-ALK is the most common ALK rearrangement that we see among NSCLC patients. These rearrangements occur on chromosome 2p23 as the fusion between the 5′ end of the EML-4 gene, and the 3′ end of the ALK gene involves nine different fusion variants. The drugs used for targeting these genetic changes include Alectinib, Brigatinib, Ceritinib, Crizotinib, and Lorlatinib.
It is the protooncogene showing regulated signal transduction serine/threonine-protein kinase, which integrates towards promoting cell proliferation and survival. Researchers observe somatic mutations of BRAF among almost 1-4% of all NSCLC patients, mainly among the adenocarcinoma patients 22–24.
It is an advanced treatment of cancer that mainly utilizes the body’s natural defense to fight against cancer. Some of the cancerous cells show similar characteristics to healthy cells. Thus, the doctors don’t observe any differentiation of the immune system between the body’s normal and abnormal cancerous cells 25. It usually works by boosting the immune system to target the cancerous cells or obstruct the growth of cancer cells by preventing its metastasis to other parts of the body and helping the immune system increase its effectiveness.
The doctors are observing improved survival rates while associating with the solid antitumor immune response. Growing numbers of CD4+ T cells, CD8+ T cells, natural killer cells, and dendritic cells interlink with a better survival rate among the patients. Also, newer strategies in immunotherapy have targeted immune-modulating mechanisms for helping the tumor cells to show defense mechanisms against the immune system. The treatment of immunotherapy showing toxicity mainly depends upon the severity and involvement of the specific organ system. Doctors recommend corticosteroid therapy for eliminating symptomatic toxicity.
Treatment by stage of non-small cell lung cancer (NSCLC)
Doctors recommend various treatments for specific stages of NSCLC. The doctors make a particular treatment plan by analyzing the patient’s cancer stage and other related factors. Also, doctors recommend clinical trials for each stage of cancer.
Stage I and II of NSCLC
Surgery can treat NSCLC stage I and II. The patients must meet the oncologist before and after the surgery. Some of the patients with large tumors and metastasis towards the lymph nodes also show advantages in the chemotherapy. Chemotherapy that doctors recommend before the surgery, is neoadjuvant chemotherapy. Even after the surgery, patients get chemotherapy to reduce cancer relapse. NSCLC patients with stage IA, wholly removed from the surgical approach don’t get Adjuvant chemotherapy with cisplatin. The NSCLC patients with stage IB cancer need to communicate with their doctors for opting for chemotherapy whether it is appropriate after the surgery or not.
For three years, the NSCLC patients with stage IB cancer and activating EGFR mutation undergo targeted therapy with adjuvant osimertinib. NSCLC patients with stage II get Adjuvant cisplatin dependent chemotherapy which the doctors entirely remove by surgery. In the case of activated EGFR mutation among the stage II NSCLC patients, doctors recommend the treatment with atezolizumab for up to 1 year. Doctors give radiation therapy to the NSCLC patients with phases I and II who cannot tolerate the surgical procedure that is stereotactic ablative radiotherapy (SABR) or stereotactic body radiotherapy (SBRT).
Stage III NSCLC
Although more than 30,000 individuals diagnose with stage III NSCLC every year, no appropriate treatment is still there for these patients. The treatment options for the NSCLC patients with stage III entirely depend upon the size and location of the tumor and the involved lymph nodes. When doctors give chemotherapy and radiation therapies together, it is concurrent chemoradiotherapy. When they give it one after the other, is sequential chemoradiotherapy.
The concurrent chemotherapy has been effective for NSCLC patients with stage III using the combination of platinum-based chemotherapy involving cisplatin plus etoposide, carboplatin plus paclitaxel, cisplatin plus pemetrexed, or cisplatin plus vinorelbine. The immunotherapy with durvalumab is provided to the patients with stage III for one year if the concurrent immunotherapy has slowed or stopped the growth of cancer cells. Moreover, professionals give systemic therapy using chemotherapy or chemoradiotherapy to stage III NSCLC patients if surgery is the only option. After surgery, doctors also give adjuvant platinum-based chemotherapy and osimertinib or atezolizumab, mainly for individuals with EGFR mutations.
Stage IV NSCLC
The NSCLC patients with stage IV mainly do not undergo surgery and radiation therapy as their primary treatment. Doctors also give whole-brain radiation therapy (WBRT) if cancer has spread to the brain region. Doctors also recommend radiation therapy and surgery for NSCLC patients with cancer spread to the adrenal gland and other local areas, causing severe pain. We also give Systemic therapies to Patients with stage IV NSCLC as they have a higher risk of getting cancer in other body parts. Chemotherapy, targeted therapy, or immunotherapy are the most common systemic therapies provided in such cases. Also, palliative care is effective in this case.
- Ramalingam S, Belani C. Systemic Chemotherapy for Advanced Non-Small Cell Lung Cancer: Recent Advances and Future Directions. The Oncologist. Published online January 1, 2008:5-13. doi:10.1634/theoncologist.13-s1-5
- Masters GA, Temin S, Azzoli CG, et al. Systemic Therapy for Stage IV Non–Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. JCO. Published online October 20, 2015:3488-3515. doi:10.1200/jco.2015.62.1342
- Kelly K, Crowley J, Bunn PA Jr, et al. Randomized Phase III Trial of Paclitaxel Plus Carboplatin Versus Vinorelbine Plus Cisplatin in the Treatment of Patients With Advanced Non–Small-Cell Lung Cancer: A Southwest Oncology Group Trial. JCO. Published online July 1, 2001:3210-3218. doi:10.1200/jco.2001.19.13.3210
- Scagliotti GV, De Marinis F, Rinaldi M, et al. Phase III Randomized Trial Comparing Three Platinum-Based Doublets in Advanced Non–Small-Cell Lung Cancer. JCO. Published online November 1, 2002:4285-4291. doi:10.1200/jco.2002.02.068
- Schiller JH, Harrington D, Belani CP, et al. Comparison of Four Chemotherapy Regimens for Advanced Non–Small-Cell Lung Cancer. N Engl J Med. Published online January 10, 2002:92-98. doi:10.1056/nejmoa011954
- Fossella F, Pereira JR, von Pawel J, et al. Randomized, Multinational, Phase III Study of Docetaxel Plus Platinum Combinations Versus Vinorelbine Plus Cisplatin for Advanced Non–Small-Cell Lung Cancer: The TAX 326 Study Group. JCO. Published online August 15, 2003:3016-3024. doi:10.1200/jco.2003.12.046