Better Detection, Surgery, Systemic Therapies Improving Cure Rates in Early-Stage Lung Cancer

Jenny White had doused the bathtub tiles at her home in Nashville, Tennessee, with an ammonia-based cleaner when she noticed a mold stain on the ceiling. She spritzed some bleach on the stain. As she waited for the bleach to soak in, she started coughing. So she opened a window. Then she coughed some more. She pulled her T-shirt up over her nose. But the coughing and wheezing had become unbearable. Still not quite right the next day, White went to see her family doctor. The doctor ordered a chest X-ray to rule out chemically induced pneumonia from the toxic cocktail of ammonia and bleach she had inhaled.

White didn’t have pneumonia, but the X-ray revealed a spot on her right lung that the doctor wanted to monitor through quarterly CT scans for the next two years.

“If, at the end of that two-year period, what you’re watching has not grown, then they call it a benign calcification,” White says. This was 2009. A September 2010 scan revealed that the spot on her lung had grown by 30 percent. It would have to be removed.

PHOTO BY SARAH BAILEY

JENNY WHITE was treated with surgery and a targeted drug for her stage 1a lung cancer. [PHOTO BY SARAH BAILEY]

Early Detection

A minimally invasive surgery found that 49-year-old White had stage 1a non-small cell adenocarcinoma in the upper lobe of her right lung. When found at all, early-stage lung cancers like White’s are typically discovered by chance after a doctor orders a chest X-ray for some other reason. But low-dose spiral computed tomography (CT) now makes it possible to screen people at high risk for lung cancer before they ever show signs or symptoms, something that is recommended by the U.S. Preventive Services Task Force and is being widely taken up by the health care community. As cases are detected earlier, doctors have more opportunities to offer potentially life-saving treatments through improved surgery and radiation techniques and new drugs.Until recently, detecting lung cancer at an early, more treatable stage was a rare or chance event. Symptoms of lung cancer — such as coughing or chest pain – that would prompt a doctor to order a chest X-ray are usually the signs of more advanced disease.

“Once the patient has symptoms from the cancer, their cure rates go way down, and we don’t really have a good marker to identify those folks earlier,” says Corey Langer, director of thoracic oncology at the Hospital of the University of Pennsylvania.

A chest X-ray can detect a tumor on the lung about the size of a dime. The newer screening technique of low-dose spiral CT can find tumors the size of a grain of rice. Using CT scans instead of X-rays could reduce lung cancer mortality rates by up to 20 percent in those screened.

In a study of 53,000 heavy smokers between the ages of 55 and 74, researchers compared the lung cancer mortality rates of those who underwent routine chest X-rays to those who had low-dose spiral CT scans. About one in four CT scans came back positive for abnormalities that could be lung cancer, while only about one in 15 X-rays raised such red flags. Over about seven years of observation, the CT group saw three fewer deaths per 1,000 screened than the X-ray group. But the screening method is not perfect. With spiral CT, like chest X-ray, about 95 percent of positive results turn out to be false. Although some of these are resolved with additional and follow-up imaging, many undergo surgery for a benign lesion. According to the Mayo Clinic, 15 to 25 percent of surgeries done as follow-ups to positive CT scans reveal benign lesions. Also, for now, only heavy smokers on the order of a pack a day for 30 years or more are eligible for the screening.

“What about the 20 percent who get lung cancer who never smoked, or those who have less than 30 pack-years? We don’t have proof of a screening technique in those individuals,” Langer points out.

Small Cell Lung Cancer

The scan also rarely detects small cell lung cancer, which accounts for about 15 percent of lung cancers, grows and spreads more quickly than non-small cell, and is more often caused by smoking.Doctors seldom diagnose small cell lung cancer early enough that it can be removed through surgery. It is typically diagnosed at either limited or extensive stage. Limited-stage small cell lung cancer is found in only one lung and the nearby lymph nodes. Extensive stage has spread to other parts of the chest or other parts of the body.

“Unfortunately, the treatment options for small cell remain the same in 2015 as they were in 2005 and 1985,” Langer says.

People with limited-stage disease typically receive a combination of chemotherapy and radiation. The standard chemotherapy drugs in this case are etoposide and cisplatin. For extensive-stage disease, people usually receive the same chemotherapy regimen but without radiation. Because lung cancer often spreads to the brain, people who respond to chemotherapy may, after finishing that regimen, receive preventive radiation to the brain.

“Limited small cell is curable — at least for a quarter to a third of patients,” Langer explains. “Concurrent chemo and radiation can result in long-term and meaningful survival.”

While little has changed in the treatment landscape for this form of lung cancer, a targeted therapy may one day improve survival rates for some people. Targeted drugs can shut down a step in the process of cancer development. In an early trial, rovalpituzumab tesirine (Rova-T) has proven to destroy small cell lung tumor-initiating cells that are positive for the DLL3 protein, potentially creating a new treatment option for patients whose small cell lung cancer progresses or recurs after initial therapy.

Non-Small Cell Lung Cancer

Also being explored in the clinic are additional targeted drugs, such as the tyrosine kinase inhibitor Iclusig (ponatinib), which is approved for use in leukemia; drugs that stop blood vessel growth to tumors such as Avastin (bevacizumab); and immunotherapies, including vaccines and a drug already approved in non-small cell lung cancer that frees up the body’s own immune system to fight cancer, Opdivo (nivolumab).Non-small cell lung cancer accounts for about 85 percent of lung cancers. The roughly 10 to 20 percent of lung cancers that develop in non-smokers, like Jenny White, are more often non-small cell.

Adenocarcinoma, the kind of non-small cell lung cancer White had, is the most common form of lung cancer. Though most people who get this and other lung cancers are smokers or former smokers, when non-smokers do get lung cancer, it’s usually adenocarcinoma. This form of the disease, which develops on the outer parts of the lungs, grows more slowly than other forms, so it’s more likely to be found before it spreads beyond the lung. Squamous cell — or epidermoid – carcinoma grows inside the bronchial tubes. Large cell carcinoma describes nonsmall cell lung cancers that are neither adenocarcinomas nor squamous cell carcinomas. They grow and spread more quickly than the other non-small cell lung cancers.

Surgery Alone

Doctors typically describe cancer stage by its TNM classification: T for the size of the tumor, N for the extent to which the lymph nodes are involved, and M for whether the cancer has metastasized, or spread, to other parts to of the body. Earlystage lung cancers are N0 or N1, because they may only include the nearby lymph nodes, and M0 (zero) because they have not metastasized.Non-small cell lung cancers in stages 1a or 1b that have not spread to the lymph nodes (N0) and in which the tumor is no larger than 4 centimeters (T1-T2a) may be cured with surgery alone. Several minimally invasive options exist for these cancers.

White had video-assisted thoracoscopic surgery (VATS). In VATS, the surgeon inserts a tiny camera into the chest. The target area, either for biopsy or excision, is shown on a monitor so that the surgeon can remove the tissue through tiny incisions. Should surgeons need to remove any lymph nodes that the cancer has reached, they can do so through VATS as well.

Minimally invasive robotic surgery may also be an option. In this method, the surgeon sits at a console near the patient and operates the surgical instruments with controls. Studies have shown that this surgery is as effective as VATS.

“Although the incisions are small, it’s been difficult to show that the outcomes are actually better than in more conventional surgery,” says Jack Roth, chief of thoracic molecular oncology in the Department of Thoracic and Cardiovascular Surgery at MD Anderson Cancer Center in Houston, Texas.

Radiation Instead of Surgery

That’s in part because even conventional open thoracic surgery is less invasive than it once was, Roth says. “It’s now done without cutting muscles and without cutting ribs,” he says. “Everything has moved in the direction of less invasion for the patient, less tissue destruction and better pain management.”Not all lung tumors are operable. Traditionally, doctors have recommended radiation for tumors that cannot be removed due to their size or location or for patients who are not healthy enough for surgery. Over the last 10 years, a newer form of radiation therapy, called stereotactic ablative radiotherapy (SABR), has been shown to be a more efficient alternative to traditional radiation for people with inoperable tumors. It can deliver an extremely high dose of radiation directly to the tumor while applying very little radiation to the surrounding healthy tissue.

Surgery and Chemotherapy

“Low-dose radiation beams come in from multiple directions and converge on the tumor, while the normal tissue is spared,” says Roth. This year, Roth co-led a small clinical trial, including 58 patients, that showed that SABR was as effective as, and perhaps better than, surgery in treating small tumors in stage 1a lung cancer. Larger trials to test this concept are in the works.Stage 2a and 2b lung cancers include tumors larger than 7 centimeters (T3) that have not spread to the lymph nodes (N0) or tumors up to 7 centimeters (T1a — T2b) where cancer may have spread to the nearest lymph nodes (N1).

For lung cancer at these stages, doctors may recommend four rounds of chemotherapy after surgery. This is called adjuvant chemotherapy, and it’s intended to help prevent recurrence. Doctors usually prescribe a platinum-based drug, such as cisplatin or carboplatin, and one other drug or “partner agent.”

“In early-stage, curative treatment, the data support cisplatin over carboplatin,” Langer says. “I will only use carbo if the patient is not up to cisplatin.” Of the two drugs, cisplatin is known for more severe side effects, including nausea, vomiting, nervous system damage, kidney damage, hearing loss, and reduced production of red blood cells, white blood cells and platelets.

Typical partner agents include paclitaxel, docetaxel, gemcitabine or vinorelbine. Some doctors recommend Alimta (pemetrexed) instead of other partner drugs for adenocarcinoma of the lung.

Tumor Genotyping and Targeted Therapy

While later-stage lung cancers are often found because patients have symptoms, some stage 3 disease is found through screening. Treatment for stage 3 cancers involves a multi-modality approach, but can vary quite a bit depending on individual details. It can include surgery and a targeted drug, or various combinations of chemotherapy, radiation and/or surgery.Doctors can analyze the genes in tumors removed through surgery to predict whether patients will benefit from particular drugs. In a group of ongoing trials, known together as ALCHEMIST (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials), researchers are exploring the benefits of targeted drugs already approved for later-stage lung cancers in people with earlier-stage disease. In two of the ALCHEMIST studies, researchers want to learn whether the targeted drugs can prevent or delay lung cancer recurrence in those who have undergone treatment for earlier stages of the disease.

The trials include patients whose tumors were completely removed at surgery and who have completed any post-surgery chemotherapy or radiation that their doctors prescribed. In one trial, participants’ tumors have a specific abnormality of the ALK gene, which experts believe plays a role in cancer growth. About 5 percent of people with certain types of non-small cell lung cancer have tumors with this particular gene defect. 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 whose tumors have a known mutation of the EGFR gene, which may also play a role in cancer growth. Participants in this trial receive placebo or Tarceva (erlotinib), which blocks EGFR activity.

White’s tumor had the relevant EGFR mutation, and her doctor prescribed a regimen similar to that in the ALCHEMIST trial, although it is not considered standard. White took Tarceva for six months after her surgery to eliminate any microscopic cancer cells that may have been left behind after her surgery, she says. While the drug itself didn’t bring White any serious side effects, she was not allowed to take her acid reflux medication while she was taking the targeted therapy.

Immunotherapy for Early-Stage Non-Small Cell Lung Cancer

“I was pretty miserable from GI upset during that time,” she recalls. Today, White remains cancer-free.Soon ALCHEMIST will be amended to offer immunotherapy drugs to those who did not have one of the genetic abnormalities necessary to receive Xalkori or Tarceva. Study participants will be randomly assigned to receive Opdivo (nivolumab), a drug already approved for advanced non-small cell lung cancer, versus observation, says Langer, who is an investigator on the trial.

Moving Forward

Opdivo blocks PD-1, a protein found on immune cells that serves as the brakes for the immune system. The immune system attacks foreign cells that pose a threat. PD-1 prevents the system from flaring up and attacking every innocuous unknown cell it encounters. Many cancer cells take advantage of this brake system and carry a corresponding protein, PD-L1, that signals immune cells to put on the brakes and let the cancer cells slip by. Opdivo takes the foot off these PD-1 brakes, unleashing the immune system on cancer cells.Studies suggest that every lung tumor should be genotyped after removal, and some cancer centers are following suit. “We try to use genomic testing on all the patients where we have tumor available. Certain types of treatment are dictated by genomic results,” says Roth.

New detection techniques help diagnose lung cancer when it’s at a far more curable stage, but surgery and radiation alone do not cure everyone. Targeted and immune therapies at these stages may lead to more cures.

C

“In early-stage lung cancer, the majority of patients are cured, but there’s still about 30 percent of patients whose tumors recur and who, as a result, ultimately die of their disease,” Roth says. “We still have room for improvement in treating early-stage lung cancer, with systemic agents, not just surgery and radiation therapy.”