Carefully Staged: Advances in Early Stage Lung Cancer

CURELung Special Issue
Volume 1
Issue 1

Potentially curative therapy for each stage of early lung cancer is evolving.

Cyndi Price had been having some trouble breathing and went to her family physician in High Point, North Carolina. Thinking she might have pneumonia, the doctor sent her out for a chest X-ray. The report came back mixed — she had fluid in her lungs that was, in fact, caused by pneumonia, but there was also a suspicious shadow on her lower left lung.

“He called me, set-up a CT scan for Tuesday and that night called me to tell me there was definitely something there that they had to follow up,” says Price. “By Wednesday, I had a PET scan, on Friday I had seen a thoracic surgeon, and the next Tuesday I had surgery, followed by chemotherapy about a month later.”

In the cancer arena, Price’s is not an unusual story. Lung cancer is the second most common cancer in both men and women and the leading cause of cancer-related death. About 14 percent of all new cancers originate in the lungs, and the American Cancer Society estimates there will be about 224,000 new cases in 2016 and 158,000 deaths from the disease.

Like most with this disease, Price has non-small cell lung cancer (NSCLC), for which several novel treatments have been approved and more are on the horizon. Only 15 percent of cases are diagnosed as small cell lung cancer (SCLC), which has different characteristics and fewer treatment options.

What is unusual about Price’s experience is that her disease was diagnosed at an early stage, 1b. When this happens, it’s usually because the cancer is discovered by accident when the chest is screened for an unrelated reason. In fact, most lung cancers aren’t diagnosed until they have spread, because that’s when they tend to become symptomatic — although there’s hope that more lung cancers will be found early now that routine CT screening is recommended for current and former heavy smokers.

Early diagnosis represents an opportunity, since lung cancers are potentially curable in stages 1, 2 and sometimes 3. As a result, it’s vital that these patients be treated by specialists in the disease, possibly with backup from multidisciplinary teams that can carefully consider which combinations of surgery, medication and radiation therapy are likely to work best.


Some SCLCs are described as “limited stage,” meaning the cancer is found only on one side of the chest and involves a single part of the lung and possibly some nearby lymph nodes. Some of these cancers are curable. “Extensive stage” is when the cancer has spread into both lungs and/or has metastasized to other parts of the body.

“Treatment for SCLC is often limited, since the majority of patients don’t get diagnosed until they are in the later stages of the disease,” says Varun Puri, associate professor and associate program director of the cardiothoracic surgery resident program at Washington University School of Medicine, in St. Louis. “In that instance, surgery has minimal to no application, and chemotherapy or radiation are most commonly employed. For those found in an early stage, surgery is much more successful and can be followed by chemotherapy.”


There are three main types of NSCLC:

> Adenocarcinoma, which starts in the glands of the body, is the most prevalent type among both men and women, and can occur in either smokers or non-smokers.

> Squamous cell carcinomas begin in newly forming squamous cells, the flat cells found along the airways inside the lungs, typically in smokers.

> Large cell carcinomas are usually diagnosed by excluding adenocarcinoma, squamous cell and small cell cancers, and often spreads quickly.

The staging of NSCLC is much more involved than in SCLC.

> In stage 1, the cancer is found only in the lungs and has not spread to any of the lymph nodes.

> In stage 2, there is lymph node involvement, but only in those near the tumor.

> Stage 3 is diagnosed when cancer is found in the lymph nodes toward the middle of the chest. It is more specifically typed as stage 3a when it is found in lymph nodes on the side of the chest where the cancer started, or 3b when it has spread to lymph nodes on the other side of the chest or above the collarbone.

> Stage 4 cancer is diagnosed when the disease has spread to both lungs, to fluid around the lungs or to another part of the body.


“The treatment for each stage is different,” says Chao H. Huang, director of thoracic oncology at the University of Kansas Medical Center. “A diagnosis at stage 1 is usually treated with surgery unless the patient is too sick or frail for anesthesia or surgery. Stage 1 cancers with a nodule bigger than 4 cm, or stage 2, may get a combination of radiation and/or chemotherapy, known as ‘neoadjuvant therapy,’ to shrink the tumor before surgery. Alternatively, patients with larger tumors who undergo surgery up front should also receive chemotherapy afterwards as ‘adjuvant therapy’ to help decrease risk of recurrence.”

For those with stage 3 disease, treatment decisions are more complex and depend on factors such as location of the tumor, the patient’s overall health, lung function and if the patient has a preference among possible therapies. Treatment could be a combination of chemotherapy and radiation therapy given together, sometimes followed by surgery in those who are surgical candidates. But for most, chemotherapy and radiation without surgery are the usual treatment.

When it comes to chemotherapy, lung cancers have mainly been treated with platinum-based medications, including cisplatin and carboplatin. After surgery in earlier stages of lung cancer, one of these drugs is typically paired with a “partner” agent: paclitaxel, docetaxel, gemcitabine or vinorelbine. Specifically for adenocarcinoma, some doctors prefer using Alimta (pemetrexed) as the partner drug, which causes fewer side effects. Side effects of these chemotherapy regimens can include nausea and vomiting, swelling in the hands and feet, fatigue, lowered white blood cell and platelet counts, and diarrhea.

New combinations of chemotherapies are being studied in clinical trials. In addition, researchers are considering lab tests that look for certain genes that might help determine in advance whether someone would benefit from chemotherapy in general, or even from a specific type of chemotherapy.


The second leg of the NSCLC triad is radiation therapy. This strategy, too, has undergone changes in both application and results. Although most early-stage (stage 1 and some stage 2) cancers are treated with surgery, some patients are too sick or frail to tolerate anesthesia. These, and those with more advanced cancers, are candidates for focused radiotherapy.

“The emerging paradigm in these patients is to use a specific type of radiation instead of resection,” says Thomas J. Dilling, director of thoracic radiotherapy at Moffitt Cancer Center in Tampa. “Previously, the treatments were at low doses, five times a week for many weeks. This was not giving a high enough dose of radiation to actually kill the cancer, so we were seeing only about a 50 percent chance of cure.” Called stereotactic radiation, the dosing has been changed so that it involves fewer treatments at higher doses than conventional radiation. Dilling likens it to giving the tumor a big knock-out punch instead of many slaps in the face. This can result in cure rates as high as 90 percent for cancers that have not spread to the lymph nodes.

Side effects of radiation to the lungs and/ or chest can include nausea and vomiting, fatigue, skin changes and hair loss in the area being treated, cough, shortness of breath and sore throat.

Radiation oncologists are also integrating newer imaging into their practices for NSCLC. Positron Emission Tomography (PET) scans use a radioactive tracer as contrast. The more metabolically active an area is, the more of the tracer it absorbs.

“In the past, we tried to hit every lymph node in the chest, fearing that if we left one untreated, the cancer would regrow,” says Dilling. “We use the scan to find nodes that have active cancer and target only those regions, sparing other lymph nodes in the chest. This makes it significantly less toxic without reducing the cure rate.”

Genetic profiling may soon have a use in radiation therapy as well.

“Tumors are genetically distinct in how sensitive they are to radiotherapy,” says Dilling. “An assay is now in development at Moffitt that may give us guidance on how to lower the dose for some, while identifying those others who might be better off with higher doses.”


Newer surgical techniques for lung cancers have helped lessen the trauma associated with removing parts of the lung that have tumors. Minimally invasive surgeries mean that smaller incisions are needed. This is most often used in stage 1 cancers. “For stage 1 cancers, the gold standard is removal of the lobe of the lung that contains the tumor, called a lobectomy,” says Puri. “In those with other medical problems that make surgery too dangerous, we can remove a smaller part of the lobe in a segmentectomy.”

For either patient, this is usually done using a minimally invasive approach. Instead of the 4- to 6-inch incision used in open surgeries, a minimally invasive approach requires one to three small punctures. It greatly reduces recovery time, there is less risk for infection, the ribs don’t have to be separated to get to the lung and there is less blood loss. One way this can be performed is through video-assisted thoracic surgery (VATS), during which physicians insert a long, thin tube with a video camera at the end. Another incision nearby allows instruments into the chest cavity to cut out and remove a part of the lung. Most patients are able to return home after only two or three days in the hospital. Another option is use of a robotic surgery device. Again using tiny incisions, the surgeon can control the robot from a console in the operating room. Because of three-dimensional video screens, the doctor has a better view of the area and improved ability to find and remove lymph nodes during the operation. “Around 50 to 55 percent of operations for early-stage lung cancer in the U.S. are minimally invasive,” says Puri. “For stage 2 disease, we usually will consider minimally invasive surgery. However, if you have a lymph node with cancer that is near a blood vessel or other important structure, the surgeon will often go with an open surgery to assure a safe and complete cancer operation.”

If the diagnosis is stage 3, induction therapy may be used. In this instance, chemotherapy or radiotherapy are used to shrink the tumor before removal.


In some cases, the ability to genetically profile an individual’s cancer cells is allowing doctors to personalize treatment, using novel medications to specifically target an abnormality that is causing the cell to grow uncontrollably while avoiding some of the side effects that might come with chemotherapy or radiation.

“Not all tumors are the same; there are often genetic differences that impact on treatment,” says Huang. “We are now able to look at a patient’s tumor and often see what mutations or abnormalities have occurred that triggered the cancer. Then, oncologists can find specific drugs that best fit a person’s specific cancer.”

Targeted drugs are mainly approved for use in advanced, or stage 4, NSCLC, although one, Avastin (bevacizumab), which stops blood vessel growth to tumors, is approved for firstline use — in combination with chemotherapy — in unresectable or locally advanced NSCLC, as well as for more advanced disease.

In addition, many targeted drugs are being studied for potential use in earlier-stage disease.

For instance, a group of trials known as ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials) is asking whether patients who have undergone treatment for early-stage lung cancer might benefit by following that with targeted drugs in order to prevent recurrence. Enrolled are patients who underwent surgery to completely remove their tumors, and then completed post-surgery chemotherapy or radiation as prescribed by their doctors.

One of these trials includes patients whose tumors are driven by a problem with the ALK (anaplastic lymphoma kinase) gene, which is rearranged, sparking cancer cells to grow. This genetic rearrangement, which affects about 5 percent of people with certain types of NSCLC, causes excessive growth and spread of cells. In this trial, participants receive either placebo or Xalkori (crizotinib), a drug that blocks the cancer-promoting activity of the ALK abnormality.

Another component of the trial includes people with NSCLC who have a mutation in the gene controlling the activity of epidermal growth factor receptor (EGFR). EGFR causes a healthy cell to remain turned on and constantly stimulates the cells to grow and divide, but can be shut off by the cell’s control mechanism. When a mutation causes the receptors to be overactive, it continues to grow and divide past when it normally would have stopped.

“There are a group of medicines known as EGFR tyrosine kinase inhibitors that can shut off this switch telling the cancer to grow,” says Huang. “If the mutation is present, it tends to be the dominant one, and tumors respond dramatically to these medications.”

Participants in this ALCHEMIST trial receive placebo or Tarceva (erlotinib), which blocks EGFR activity. In addition, Tarceva and other EGFR-targeting drugs, such as Gilotrif (afatinib) or Iressa (gefitinib), have been, or are being, looked at in other clinical trials of patients with early-stage lung cancer. These trials consider whether treatment with EGFR-targeting drugs either before or after surgery will improve outcomes.

The side effects of drugs that target EGFR or ALK can include rash, nausea, diarrhea, mouth sores, shortness of breath and fatigue.

Targeted drugs are also being explored in the clinic to treat SCLC, including the tyrosine kinase inhibitor Iclusig (ponatinib), which is approved for use in leukemia, and drugs similar to Avastin.

Like many current or former smokers, Price was found not to have any mutations that are targetable by existing drugs. “I did genetic testing twice: once when I had my surgery, and when I started treatment again,” says Price, who smoked a pack of cigarettes a day for 41 years. “If patients did not have genetic testing initially and they have a recurrence, genetic testing is still available. My genetic testing revealed I had no targetable genes, but this can change (as more targets and more drugs emerge).”


Attempts to bolster the immune system, known as immunotherapy, so that the body can fight off the cancer have also been useful in expanding treatment options — but, again, specifically in advanced lung cancers.

One way to do this is through the use of checkpoint inhibitors. These drugs have activity against molecules on an immune cell that need to be turned either on or off to start an immune response. Cancer cells can use these checkpoints to avoid being attacked by the immune system. Newer treatments targeting these checkpoints leave cancer cells more exposed to the body’s normal defenses.

Opdivo (nivolumab) and Keytruda (pembrolizumab) block a protein (PD-1) that keeps immune cells known as T cells from attacking other cells in the body. This allows those immune cells to recognize and respond to cancer cells, shrinking tumors and slowing their growth. These types of drugs — which can cause side effects including fatigue, rash, cough, nausea, diarrhea, itching, joint pain, upper respiratory tract infection and swelling of the extremities — are approved for the treatment of stage 4 NSCLC, but trials will be investigating them for use in earlier-stage disease. In fact, ALCHEMIST will soon be amended to offer immunotherapy drugs to those who did not have one of the genetic abnormalities necessary to receive Xalkori or Tarceva in the trials. Study participants will be randomly assigned to receive Opdivo versus observation.

Meanwhile, the European STIMULI trial will test Opdivo and another immunotherapy, Yervoy (ipilimumab), in patients who have limited-stage small cell lung cancer. The phase 2 trial will compare standard chemoradiation alone versus chemoradiation followed by the immunotherapies.

Of course, either targeted treatments or immunotherapies can be the go-to drugs for some patients whose lung cancer is caught early, but later progresses to an advanced stage. Price turned out to be one of them.

After her initial treatment, Price’s lung cancer went into remission. However, the cancer returned, along with a small tumor in her brain. She tried a second course of standard chemotherapy for her lungs, but problems with her kidneys cut those short. Radiation was prescribed for the brain tumor, and she underwent 10 treatments.

Her doctor then suggested that Price follow that treatment with Opdivo. So far, there has been no growth in either her lung or brain tumors since starting this round of treatment. It’s a therapy she appreciates, she says, for its ability to stimulate her immune system without causing the kinds of major side effects chemotherapy can bring.

“With this new treatment, my tumor is not getting any bigger,” Price says. “I told my oncologist that I was on a 10-year plan of things I wanted to do. He said I should start thinking about what I will be doing 20 years from now.”