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Lung Cancer

Conventional Treatment

Lung cancer treatment depends on the subtype of the cancer and its stage. The initial treatment for stage I or II NSCLC is surgery, usually followed by chemotherapy and radiation. Although surgery in patients with stage III cancer is controversial, national guidelines suggest its use in certain cases (McCloskey 2013). Either way, these patients will generally receive chemotherapy and often drugs that specifically target signaling pathways known to be involved in lung carcinogenesis such as bevacizumab (Avastin), erlotinib (Tarceva), or crizotinib (Xalkori) (NCCN 2014a; ACS 2013a).

Early-stage (stage I) SCLC may be treated with surgery to remove the affected lobe followed by chemotherapy, with a combination of chemotherapy and radiation, or chemotherapy alone (ACS 2014d). More advanced SCLC is often treated with chemotherapy alone or with radiation therapy to the whole brain (to treat/prevent metastasis) or other parts of the body to shrink tumors and reduce symptoms (NCCN 2014b).

Surgery

Surgical removal of a primary lung tumor by a thoracic surgeon is the standard treatment for early-stage NSCLC (Belani 2005; He 2012; NCCN 2014a; Liberman 2006). The preferred method is anatomic pulmonary resection (thoracotomy), also called pneumonectomy or segmentectomy depending on how much lung tissue is removed. It is the most common surgical procedure in general thoracic surgery. It can be performed with a minimally-invasive approach called VATS (video-assisted thoracoscopic surgery) (He 2012; NCCN 2014a). An advantage of VATS is that it requires only a minimal incision in the thorax. Thus, it takes less time to perform the surgery, with fewer post-surgical complications and faster recovery (Detterbeck 2013; NCCN 2014a).

Only about 5% of patients with SCLC are diagnosed at stage I, which is the only stage for which surgery is an option (NCCN 2014b).

More than half of patients with either type of lung cancer are not eligible for surgery due to local spread (ie, extended beyond the lungs into the thoracic cavity) or distant metastasis (Shamji 2013). Other contraindications include patient age (particularly 75 and older), general physical and mental health, and certain characteristics of the cancer. In addition, the patient may elect not to undergo surgery (Dell'amore 2013; Shamji 2013; Mehta 2012).

Readers are encouraged to also review the Cancer Surgery protocol, which contains detailed information about important considerations for those preparing to undergo surgery to remove cancerous tissue.

Radiation Therapy

Radiation therapy may be administered alone or in combination with chemotherapy and/or surgery, depending on the type of lung cancer, stage, and the presence and nature of complications. In combination with surgery, a regimen of radiation therapy is designed to maximize lung cancer cell killing in the surgical zone (ie, area of the tumor that will be removed). Radiation therapy may be given before surgery (neoadjuvant therapy) to shrink the tumor before the surgical procedure or after surgery (adjuvant therapy) to destroy tumor cells that were left behind (O’Hanlon 2013).

NSCLC. Radiation can be used in NSCLC patients who undergo surgery, as a primary treatment modality when surgery cannot be performed, postoperatively when the cancer was not completely removed, or as a palliative treatment to help keep the patient comfortable (O’Hanlon 2013).

SCLC. In SCLC, radiotherapy administered concurrently with chemotherapy is considered the standard and preferred therapeutic approach, and a shorter time between the start of any treatment and end of radiation therapy was significantly associated with improved survival (NCCN 2014b).

In addition, in all patients, radiation therapy can be used to treat brain metastases, spinal cord compression, or local lesions that cause symptoms, such as nerve paralysis or the obstruction of airways (NCCN 2014a; O'Hanlon 2013; Baskar 2012). Cranial radiation may be implemented preventively as well; patients whose SCLC can be controlled outside of their brain have about a 60% chance of developing central nervous system metastasis within 2 – 3 years of treatment. Preventive cranial radiation therapy has been reported to substantially reduce this risk (NCI 2014a).

Conventional radiotherapy fails to control unresectable NSCLC about 70% of the time. Only around 40% of people with unresectable NSCLC who receive conventional radiotherapy survive 2 years (Ferri 2013). Radiation therapy improves survival for patients with limited-stage SCLC and is recommended soon after diagnosis (ACR 2012). It is typically delivered in conjunction with chemotherapy in patients with limited disease and for a select group of patients with extensive stage disease who respond to chemotherapy (NCCN 2014b; Provencio 2011).

High dose radiation therapy may be associated with some side effects depending on the area(s) of the body targeted. Fortunately, many modern radiation therapy techniques such as intensity-modulated radiation therapy (IMRT), helical tomotherapy, and volumetric-modulated arc therapy target cancerous tissue more precisely, reducing damage to nearby tissues and organs (Chi 2013). A form of targeted radiation therapy called stereotactic body radiation therapy is gaining attention as a useful tool for treatment of early stage lung cancer. A technique called Gamma Knife radiosurgery is used to deliver targeted radiotherapy, while sparing the surrounding healthy tissue, and has been intensively studied in the context of brain metastases originating from lung cancer (Abacioglu 2010; Serizawa 2000; Serizawa 2002). A 3-year postoperative study on 59 patients with early stage but inoperable lung cancer found a survival rate of 55.8%, with a tumor control rate of 97.6% with stereotactic body radiation therapy, about twice that found with conventional radiotherapy (Timmerman 2010).

The Cancer Radiation Therapy protocol provides a comprehensive discussion about radiation therapy and outlines a number of steps that can be taken to maximize its benefits and minimize its side effects.

Chemotherapy

Chemotherapy describes the treatment of disease with chemicals (drugs). In the case of cancer chemotherapy, the drugs administered to the patient typically cause damage to cancer cells by interfering with the process of cell division (Goodin 2007). Although chemotherapy can affect malignant and healthy cells, those cells afflicted with cancer-causing mutations tend to be more vulnerable to these medications because they grow and divide much more rapidly than most normal cells. However, certain cell types, such as those in the hair follicles, gastrointestinal tract, and oral mucosa, divide rapidly under normal conditions, thus begetting the common side effects associated with chemotherapy (Mukherjee 2010; Hanahan 2011; PubMed Health 2012). 

Chemotherapy, both in the neoadjuvant (prior to surgery) and adjuvant (post-surgical) settings remains a mainstay of lung cancer therapy (Ripley 2013; Daly 2011; Reungwetwattana 2011).

NSCLC. Patients with NSCLC undergoing adjuvant chemotherapy typically receive cisplatin (Platinol) with vinorelbine (Navelbine); carboplatin may be used in place of cisplatin in some cases, although available evidence suggests that cisplatin may be somewhat more effective (NCI 2014b). Other drugs used include gemcitabine (Gemzar), docetaxel (Taxotere), and pemetrexed (Alimta). Those receiving concurrent chemotherapy/radiation treatment are typically prescribed cisplatin and etoposide (Etopophos, Toposar), cisplatin and vinblastine (Velbe), cisplatin and pemetrexed, or carboplatin (Paraplatin) and pemetrexed (NCCN 2014a). Cisplatin is often part of neoadjuvant chemotherapy (Daly 2011).

SCLC. Patients with limited SCLC typically undergo chemotherapy with cisplatin or carboplatin with etoposide. Those with extensive stage disease may receive other regimens such as irinotecan (Camptosar, CPT-11) with cisplatin (NCCN 2014b; NCI 2014c).

Most chemotherapeutic agents are generally active in fast-growing cells, including healthy cells. They can have serious and often life-threatening side effects (such as anemia, immunosuppression, and heart damage). The Chemotherapy protocol outlines several integrative strategies that may help mitigate some of the adverse effects of chemotherapy.

Targeted Therapy

The success of treatment of NSCLC and SCLC with surgery, radiation therapy, and traditional chemotherapy is largely dependent on diagnosing lung cancer as early as possible (Daniels 2013; Yasufuku 2010; Herbst 2008). However, just a third of NSCLC cases are diagnosed in the early stages when remission with surgical resection alone is possible (Byron 2014). Even then, up to 40% of patients with stage I, 66% of those with stage II, and 75% of those with stage III NSCLC die within 5 years (Byron 2014).

In recent years, however, new classes of drugs that target signaling pathways within cancer cells and are specific to tumor type and genetic makeup provide more options for lung cancer patients, even those diagnosed in later stages (Majem 2013; Larsen 2011). They are typically used as second- or third-line treatments after traditional chemotherapy fails and are often combined with traditional chemotherapies (Majem 2013).

Targeted treatments may be determined by the molecular footprint of the tumor; thereby enabling clinicians to choose an agent based on specific mutation(s) (Table 1). For instance, patients with EGFR (epidermal growth factor receptor) mutations benefit from treatment with drugs that block pathways that activate the receptor, including erlotinib, cetuximab (Erbitux), and afatinib (Gilotrif) (NCCN 2014a; ACS 2014b; Rengan 2011; Majem 2013; Gao 2012; Domvri 2013).

Key molecular biomarkers include KRAS mutations, ALK rearrangements, and MET and EGFR immunohistochemistry, all of which can help identify sensitivity to various chemotherapies, radiotherapy, and molecularly-targeted drugs (Vincent 2012).

The ability to individualize treatment based upon the genetic profile of a patient’s tumor is ushering in a new age of personalized medicine.

Table 1.  Targeted Agents for Patients with Genetic Alterations (NSCLC) (Gadducci 2013; Pirrotta 2011; NCI 2012; Elisei 2013; NCCN 2014a; Douillard 2014; Drilon 2013)

Gene Mutations/Alterations Targeted

Available Targeted Agents

EGFR 

Gefitinib (Iressa), erlotinib, afatinib, cetuximab

ALK 

Crizotinib

HER2 

Trastuzumab (Herceptin), afatinib

BRAF 

Vemurafenib (Zelboraf), dabrafenib (Tafinlar)

MET

Crizotinib

ROS1 

Crizotinib

RET 

Cabozantinib (Cometriq)

VEGF

Bevacizumab, sunitinib (Sutent), sorafenib (Nexavar)

Bevacizumab for NSCLC. The formation of new blood vessels, known as angiogenesis, is the result of a complex equilibrium between factors that stimulate (pro-angiogenic) and factors that inhibit (anti-angiogenic) this process (Carmeliet 2000; Pallis 2013b). Normally, angiogenesis occurs during very specific times, such as development, reproduction, and wound healing, but it is also pivotal in the development of solid tumors and during their metastatic dissemination (Pallis 2013b).

Vascular endothelial growth factor (VEGF) is a protein that drives angiogenesis upon interaction with its cellular receptors (VEGF receptors). The VEGF receptor pathway is considered the most powerful mediator of angiogenesis in tumors (Das 2012; Pallis 2013b).

Bevacizumab is an antibody against VEGF; it is FDA approved for the first-line systemic treatment of unresectable NSCLC in combination with carboplatin and paclitaxel (FDA 2013; Das 2012; Ferrara 2004; Pallis 2013b; Planchard 2011; NCI 2013e). Bevacizumab is able to inhibit angiogenesis by directly binding to VEGF and preventing it from activating its receptor. In addition to NSCLC, bevacizumab has shown clinical benefits in other cancers, including breast cancer, renal cancer, and metastatic colorectal cancer (Wang 2013). Several studies suggest that combination therapies based on bevacizumab offer clinical benefits in NSCLC (Sandler 2006; Reck 2009), and long-term therapy with this compound showed benefits even in patients with late-stage NSCLC (Fan 2013). Hypertension, an increased risk of bleeding, and gastrointestinal perforation are adverse effects associated with bevacizumab treatment (Wang 2013; Planchard 2011).

Crizotinib for NSCLC. In NSCLC, mutations can occur in several different genes that can contribute to the development of the disease. One of these genes, ALK, was implicated in 2007 in a small but significant proportion of patients with NSCLC (Gupta 2014). In NSCLC, certain genetic alterations involving ALK were reported in 3-7% of patients, particularly in younger people who never smoked or were light smokers; these findings helped define a new subtype of NSCLC (Shaw 2013; Gupta 2014; Iwama 2014). In advanced NSCLC patients who previously received treatment, and who present with alterations in the ALK gene, crizotinib was found to be superior to standard chemotherapy.

Crizotinib inhibits the gene function of the gene product of ALK. It was approved by the FDA in late 2011, less than 4 years after the discovery of its target (Gandhi 2012). Adverse effects with crizotinib include nausea, diarrhea, constipation, vomiting, water retention in the extremities, and visual problems. Also, 1.6% of patients had life-threatening or fatal interstitial lung disease that was related to the treatment (Iwama 2014).

Maintenance Therapy

Maintenance therapy is a term used to refer to treatment provided once patients achieve tumor response or have stable disease. However, definitions vary slightly, and the National Cancer Institute defines it as therapy that is given to prevent the cancer from progressing once it has been successfully controlled. It may use the same drug administered previously, or a different drug, and it may include, besides drugs, treatment with vaccines or antibodies (Novello 2011; Stinchcombe 2011; Hirsh 2010). Several large trials have evaluated the use of various drugs as maintenance therapy in NSCLC patients, including docetaxel, pemetrexed, bevacizumab, erlotinib, and cetuximab, all of which demonstrated improved progression-free and/or overall survival in patients receiving the treatment, primarily those with progression-free disease. No such benefits have been observed in patients with extensive-stage SCLC (Horn 2013b).​