Treatment of lung cancer

Treatment of lung cancer refers to the use of medical therapies, such as surgery, radiation, chemotherapy, immunotherapy, percutaneous ablation, and palliative care,[1][2][3][4] alone or in combination, in an attempt to cure or lessen the adverse impact of malignant neoplasms originating in lung tissue.

Treatment of lung cancer
Specialtyoncology

Lung cancer is an extremely heterogeneous family of malignant neoplasms,[5] and well over 50 different histopathological variants are currently recognized under the most widely used typing system.[6] Because these variants have differing genetic, biological, and clinical properties, including response to treatment, correct classification of lung cancer cases are necessary to assure that lung cancer patients receive optimum management.[6][7][8]

Approximately 95% of lung cancers are carcinoma, or tumors derived from transformed cells of epithelial lineage.[9] Currently, nearly four dozen different histopathological variants of lung carcinoma are recognized.[6] For clinical and treatment purposes, however, most oncologists tend to classify lung carcinomas into two major groups, namely small cell carcinoma (SCLC) and non-small cell lung cancer (NSCLC). This is done because of differing responses to treatment—NSCLC is comparatively less sensitive to chemotherapy and/or radiation, so surgery is the treatment of choice in these tumors. SCLC, in contrast, usually initially responds well to chemotherapy and/or radiation, but has usually metastasized widely by the time it is discovered, making surgery ineffective.

In a 2010 study of patients with metastatic non–small-cell lung cancer, "early palliative care led to significant improvements in both quality of life and mood. As compared with patients receiving standard care, patients receiving early palliative care had less aggressive care at the end of life but longer survival" which was increased by approximately three months.[1]

There are typically three objectives applied to the treatment of lung cancer and can vary by patient or individual diagnosis: (1) curing lung cancer, (2) controlling lung cancer, and (3) being comfortable.[10]

Surgery
Main article: Lung cancer surgery

In most cases, the goal of lung cancer surgery is to remove the entire tumor, including a small amount of normal tissue (about 2 centimetres, 0.8 in) at the margin. The general name for surgery that enters the chest is thoracotomy, and specific named types of surgical interventions may be performed as part of the thoracotomy, such as wedge resection, segmentectomy,[11][12] "sleeve resection", lobectomy, or pneumonectomy, depending on the tumor and patient characteristics.

Surgery is very rarely used in cases of stage 3b or stage 4 non-small cell lung carcinoma.[13]

Chemotherapy

In patients with stage 3 lung cancer that cannot be removed, treatment with combined radiotherapy and chemotherapy improves survival significantly.[13]

Tumor Treating Fields might improve chemotherapy treatment.[14]

Targeted therapy
Main article: Targeted therapy of lung cancer

In recent years, various molecular targeted therapies have been developed for the treatment of advanced lung cancer. Gefitinib (Iressa; withdrawn from the U.S. market) is one such drug, which targets the tyrosine kinase domain of the epidermal growth factor receptor (EGFR), expressed in many cases of non-small cell lung carcinoma. It was not shown to increase survival, although females, Asians, nonsmokers, and those with bronchioloalveolar carcinoma appear to derive the most benefit from gefitinib.[15][16]

Erlotinib (Tarceva), another EGFR tyrosine kinase inhibitor, increased survival in non-small cell lung cancer[17] and was approved by the FDA in 2004 for second-line treatment of advanced non-small cell lung carcinoma.[18] Similar to gefitinib, it also appeared to work best in females, Asians, nonsmokers, and those with bronchioloalveolar carcinoma, particularly those with specific mutations in EGFR.[16]

The angiogenesis inhibitor bevacizumab (Avastin), (in combination with paclitaxel and carboplatin), improves the survival of patients with advanced non-small cell lung carcinoma.[19] However, this increases the risk of lung bleeding, particularly in patients with squamous cell carcinoma.

Crizotinib shows benefit in a subset of non-small cell lung cancer that is characterized by the EML4-ALK fusion oncogene,[20] and is approved by the FDA.[21] EML4-ALK is found in some relatively young, never or light smokers with adenocarcinoma.[22]

Advances in cytotoxic drugs,[23] pharmacogenetics[24] and targeted drug design[25] show promise. A number of targeted agents are at the early stages of clinical research, such as cyclo-oxygenase-2 inhibitors,[26] the apoptosis promoter exisulind,[27] proteasome inhibitors,[28] bexarotene,[29] the epidermal growth factor receptor inhibitor cetuximab,[30] and vaccines.[31] Sorafenib (marketed as Nexavar for use in renal and liver cancer) showed promise in a clinical trial matching targeted treatment to the cancer's genetic profile.[32] Future areas of research include ras proto-oncogene inhibition, phosphoinositide 3-kinase inhibition, histone deacetylase inhibition, and tumor suppressor gene replacement.[33]

Immunotherapy

Immunotherapy is a type of cancer treatment that activates the immune system to fight cancer.

In 2015, nivolumab was approved for the treatment of people with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.[34]

In 2016, the FDA approved atezolizumab for the treatment of people with metastatic non-small cell lung cancer (NSCLC) whose disease progressed during or following platinum-containing chemotherapy and pembrolizumab for the treatment of people with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test.[35][36]

In 2017, the FDA granted accelerated approval to pembrolizumab in combination with pemetrexed and carboplatin for the treatment of people with previously untreated metastatic non-squamous non-small cell lung cancer (NSCLC).[37]

In 2018, the FDA approved durvalumab for people with unresectable stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.[38]

In 2018, the FDA granted accelerated approval to nivolumab for people with metastatic SCLC with progression after platinum-based chemotherapy and at least one other line of therapy[39], and approved pembrolizumab in combination with pemetrexed and platinum-based antineoplastic (carboplatin or cisplatin) as first-line treatment of people with metastatic, NSCLC with no EGFR or ALK genomic tumor aberrations.[40]

In 2018, the FDA approved pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel as first-line treatment of metastatic squamous non-small cell lung cancer (NSCLC).[41]

In 2018, the FDA approved atezolizumab in combination with bevacizumab, paclitaxel, and carboplatin for the first-line treatment of people with metastatic non-squamous, non-small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumor aberrations.[42]

In 2019, the FDA approved atezolizumab in combination with carboplatin and etoposide for the first-line treatment of adult people with extensive-stage SCLC.[43]

In 2019, the FDA approved pembrolizumab for the first-line treatment of people with stage III non-small cell lung cancer (NSCLC) who are not candidates for surgical resection or definitive chemoradiation or metastatic NSCLC. people' tumors must have no EGFR or ALK genomic aberrations and express PD-L1 (Tumor Proportion Score [TPS] >1%) determined by an FDA-approved test.[44]

In 2019, the FDA granted accelerated approval to pembrolizumab for people with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy.[45]

Radiation

In patients with stage one or two non-small cell lung carcinoma, radiotherapy alone results in 13–39% of patients surviving to five years.[13]

Percutaneous ablation

Percutaneous image-guided ablation is a minimally invasive treatment that can be offered to patients with early stage NSCLC or for palliative treatment for patients with metastatic disease. There are various types of ablation used for treating lung malignancies including radiofrequency ablation (RFA), cryoablation, and microwave ablation. Thermal ablation is typically recommended for patients who are higher risk surgical patients due to cardiopulmonary disease. Ablation is generally a lower risk procedure compared to surgery; it requires only local anesthesia and sometimes conscious sedation, and it is minimally invasive. The procedure is performed by interventional radiology in an outpatient setting. Under CT or ultrasound guidance, a probe is advanced through the anesthetized skin until the tip of the probe is positioned within the tumor. Extreme temperature is then created through electrical current (radiofrequency ablation and microwave ablation) or gas (cryoablation), which triggers destruction of the cancerous cells. Major complications are uncommon, but include partial collapse of the lung and hemothorax. [46] While there is growing evidence supportive of ablation as treatment for NSCLC, high rates of local recurrence and new metastatic disease in the treatment areas leads to reliance on more traditional treatment modalities. The pitfalls of ablation stem from the lack of complete and homogenous destruction of tumor cells, often leading to residual malignant cells on the periphery of the tumor.[47] For that reason, lesions greater than 5 centimetres (2.0 in) should be excluded, and lesions 3 to 5 cm (1.2 to 2.0 in) should be considered with caution, given high risk of recurrence. Additionally, for safety reasons, lesions less than 1 cm (3⁄8 in) from the trachea, main bronchi, esophagus and central vessels should be excluded from RFA, given high risk of complications and frequent incomplete ablation. [48] An animal tumor model demonstrated improved survival after combined treatment with RFA and radiation therapy compared to either treatment alone. It is possible that the two modalities have a synergistic effect and patients may benefit from combined treatment.[49]

History

Prior to the early part of the 20th century lung cancer was considered a very rare disease, and all malignant lung tumors were treated identically.[50] Radical surgical resection (i.e. lobectomy[51][52] or pneumonectomy)[53] was the only effective intervention available for lung cancer prior to the 1940s, when the era of modern cytotoxic chemotherapy began.[54]

It was not until 1962 that small cell lung carcinoma (SCLC), then called "oat cell carcinoma" was recognized for its unique biological behavior, including a much higher frequency of widespread metastases at presentation, and exquisite sensitivity to cytotoxic chemotherapy and radiation.[50][55]

Early studies suggested that patients with small cell lung carcinoma (SCLC) fared better when treated with chemotherapy and/or radiation than when treated surgically.[56][57] While this approach to treating SCLC remains the current standard of care,[58] the role of surgery in SCLC is being re-examined, with recent studies indicating that surgery may improve outcomes in some patients with early stage SCLC and combined forms of SCLC and NSCLC.[59]

Trials

Squalamine is undergoing trials for treatment of non-small cell lung cancer (stage I/IIA).

In December 2012, Merck published the results of its current study. Although the Phase III Trial of L-BLP25 (Stimuvax) did not meet satisfying primary endpoints for patients with Non-Small Cell Lung Cancer, notable treatment effects have been observed for L-BLP25 in certain subgroups in the START study.[60]

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