Late-stage lung cancer

Medical oncologist David Gerber, M.D., co-leader of the lung cancer disease-oriented team
Medical oncologist David Gerber, M.D., co-leader of the lung cancer disease-oriented team, estimates that about 25 percent of non-small cell lung cancer patients have tumors with molecular profiles that respond to currently available “targeted” therapies.

The changing face of late-stage lung cancer treatment

Promising new treatment approaches—including ones developed at UT Southwestern—are steadily improving care for patients with metastatic lung cancer.

Medical therapies—chemotherapy, targeted drugs, and biological treatments—are pivotal in slowing the cancer’s growth throughout the body. Although new advances to treat lung cancer are still sorely needed, medical therapies have improved markedly in the past 20 years, says lung cancer specialist Dr. Joan Schiller, Deputy Director of Simmons Cancer Center. The latest chemotherapies are more effective and have fewer ill effects, while other medicines, like today’s anti-nausea drugs, make treatment more tolerable.

“It’s not your grandmother’s chemotherapy in terms of hair loss, in terms of nausea, in terms of fatigue,” Dr. Schiller says.

Molecular profiling—identifying genetic features of a tumor that help drive its growth—has also changed the face of lung cancer care. “We’re making strides all the time,” Dr. Schiller says, noting that drugs targeting those molecular features are oral therapies, simple for patients to take, with minimal side effects.

Dr. David Gerber, co-leader of the Cancer Center’s lung cancer disease-oriented team, estimates that about 25 percent of non-small cell lung cancer patients have tumors with molecular profiles that respond to currently available “targeted” therapies.

The most common such molecular anomaly, occurring in up to 15 percent of non-small cell lung cancers in the U.S., are EGFR gene mutations, typically found in people who smoked a little or not at all. Another anomaly occurs in the ALK gene and is found in about 5 percent of non-small cell lung cancers.

“Three to five years ago we had one class of drugs for each of these clinical scenarios. Now we have several, including second and third-generation EGFR inhibitors and second generation ALK-targeting drugs,” Dr. Gerber says.

Taken together, other, rarer molecular features of lung cancer—which individually may account for only 1 to 3 percent of cases—can also make a substantial mark on care. “These less common subtypes also provide promising opportunities that we are currently investigating,” Dr. Gerber says, citing one subset, involving an abnormality in the molecule ROS1; patients with this type of lung cancer appear to respond to ALK inhibitors. People whose lung tumors bear a BRAF mutation, or have a HER2 mutation, also may benefit from specific targeted therapies.

Testing for these rare molecular subtypes may not be common outside of an academic medical center setting, Dr. Gerber says. But because UT Southwestern belongs to the National Lung Cancer Mutation Consortium, patients’ cancers can undergo extensive molecular profiling as part of a clinical trial—meaning what could cost thousands of dollars is provided free of charge to Simmons Cancer Center patients. “Depending on the results of this molecular testing, there are associated treatment studies that allow patients access to the newest targeted therapies,” Dr. Gerber says.

Typically, UT Southwestern has around two dozen lung cancer trials open. That sets Simmons Cancer Center apart from many other treatment centers, which don’t have large volumes of lung cancer patients, says lung cancer specialist Dr. Jonathan Dowell. “We have a very large portfolio of clinical trials for essentially every stage of disease, specifically advanced disease, including firstline, second-line, and beyond, as well as for many different molecular subtypes of lung cancer that we’ve identified,” he says. “At a smaller center it’s not practical to open trials for a subset of patients who represent only a few percent of lung cancers. But here we can do that because we will see enough of those patients.”

UT Southwestern offers clinical trials for every stage of lung cancer
UT Southwestern offers clinical trials for every stage of lung cancer—many of them for metastatic disease—and for a variety of molecular subtypes of lung cancer.

Bench to bedside

Also taking the spotlight in the fight against metastatic lung cancer are biological therapies—such as the man-made antibodies cetuximab, which targets tumors with EGFR mutations, and bevacizumab, which interferes with the growth of tumor-fueling blood vessels.

Meanwhile, a promising new antibody called bavituximab, developed at UT Southwestern, is undergoing phase III testing as a second-line treatment in late-stage non-small cell lung cancers. That study will include more than 500 patients on three continents. The antibody has shown early promise when combined with conventional chemotherapy (paclitaxel and carboplatin) as a first-line treatment in patients with locally advanced or metastatic non-small cell lung cancer, Dr. Gerber says.

Bavituximab was developed by the late Dr. Phil Thorpe, a professor of pharmacology, with work continuing under collaborator and Associate Professor of Surgery Dr. Rolf Brekken. Research has found that bavituximab overcomes the immune system’s tolerance of a cancer, allowing patients to develop an anti-tumor immune response, and can also inhibit development of tumor blood vessels.

Using serial biopsies to look for immune cell infiltration of the tumor, investigators are striving to understand better in patients how those immune effects may evolve over time—as well as to elucidate the drug’s impact on tumor blood vessels.

Tailored care

A range of other care may be offered to patients with metastatic lung cancer, depending on details of their cases. In rare cases with only a single site of metastasis, surgical resection of both the metastatic site and the primary lung tumor may provide long-term disease control, says thoracic surgeon Dr. Kemp Kernstine.

UT Southwestern’s interventional pulmonologists are also available to help patients breathe easier. A pleural catheter can be implanted to drain chronic pleural fluid buildup outside the lungs. A stent can be placed to prop an airway open if a tumor is encroaching. And techniques such as electrocautery or electrosurgery can be deployed to burn away tumor tissue, or cryotherapy to freeze it away, says interventional pulmonologist Dr. Hsienchang Thomas Chiu. Patients are referred to the pulmonary medicine team by oncologists in the community as well as at UT Southwestern.

Radiotherapy can ease symptoms such as pain, bleeding, and swallowing problems. And a type of radiotherapy called endobronchial brachytherapy is now available to patients at UT Southwestern, says radiation oncologist Dr. Michael Folkert. Brachytherapy is administered via a catheter placed through the mouth, typically to treat patients who are bleeding in the airways, or to prevent a tumor from re-obstructing an airway after stenting. Additionally, percutaneous approaches, where radiation sources are placed directly into tumors via needles inserted through the skin, will soon be available for treating metastases to the liver, adrenal glands, and possibly the kidneys or lungs.

Slowing the cancer’s course

Another type of radiotherapy—which shoots highly focused beams of radiation from multiple angles at a tumor—is forestalling progression of metastatic lung cancers. UT Southwestern radiation oncologists have been leaders in developing the treatment, stereotactic ablative radiotherapy (SABR, also known as stereotactic body radiation therapy), in lung and other cancers.

In a phase II study, radiation and medical oncologists at Simmons Cancer Center and the University of Colorado treated 24 patients who had metastatic lung cancer and for whom other treatments had failed. Each patient was diagnosed with no more than six metastatic sites, other than the brain.

Doctors administered a standard drug therapy, the EGFR inhibitor erlotinib, and treated the tumors with limited courses of SABR, says UT Southwestern radiation oncologist Dr. Robert Timmerman. Instead of an expected three months, patients’ median time until progression totaled 14- plus months.

“This is a game-changer,” says Dr. Puneeth Iyengar, co-leader of the lung disease-oriented team. “Historically, once patients had stage IV lung cancer, doctors gave up trying to target areas of gross disease.”

None of the patients tested for an EGFR mutation actually had one, suggesting the therapeutic difference came from the SABR, he says.

The researchers are exploring how the treatment might spark the immune system to act against the cancer. “We used to think lung cancer is not immunogenic enough,”

Dr. Timmerman says. “It turns out lung cancer does have immune antigens that can be exploited. They’ve just been hidden inside the cells.”

At UT Southwestern, SABR is now being incorporated into stage IV lung cancer care, Dr. Iyengar says. “Our goal is to extend survival, to make this a chronic illness.”

Large-scale interest in small cell lung cancer

While non-small cell lung cancer is by far the most common form of lung cancer, 10 to 15 percent of lung cancers are the small cell type, a form of the disease that is seen almost solely in people who have smoked. Small cell lung cancer is named for the small appearance of the malignant cells under a microscope.

Because small cell lung cancer is very aggressive, it is only rarely detected in the early stages when surgery could be beneficial, says thoracic surgeon Dr. Kemp Kernstine. As with other lung cancers, when small cell cancer is caught very early, the most advanced minimally invasive surgical techniques, video-assisted thoracic surgery (VATS) and robotic VATS, may be used.

Chemotherapy and radiation therapy can both lengthen survival in patients with limited or extensive disease. Dr. Hak Choy, Chair of Radiation Oncology, notes that prophylactic cranial irradiation is administered in an effort to prevent growth of cancer that has spread undetected to the brain.

UT Southwestern has a longstanding research interest in small cell lung cancer, notes medical oncologist Dr. Gerber. “Currently, we have an ongoing effort where we’re taking blood from small cell patients and trying to identify the cancer cells in the blood, and then growing them in the laboratory to learn more about the patients’ tumors,” he says.

UT Southwestern has several trials underway for small cell lung cancer, looking at new ways to deliver radiation as well as new medicines. Recent or current trials include:

  • A PHASE III, national cooperative group trial comparing three different radiotherapy regimens, which vary in dose, frequency, and duration. The multicenter study will be conducted in patients with limited small cell lung cancer who are also receiving chemotherapy with cisplatin or carboplatin, plus etoposide.
  • A PHASE II, national cooperative group study testing prophylactic cranial radiation alone versus that plus additional radiation aimed at treating any remaining cancer elsewhere in the body. The trial is for patients with extensive disease after they receive chemotherapy.
  • A PHASE I/II study testing the addition of veliparib, a type of drug known as a PARP inhibitor, to cisplatin and etoposide chemotherapy in small cell

Treatment Approaches

Chemotherapy:

  • Combination chemotherapy
  • Chemotherapy plus monoclonal antibody treatment
  • Single-agent chemotherapy

Targeted drugs:

  • For patients with tumors harboring anomalies such as EGFR mutation or ALK rearrangement

Maintenance therapy

Radiotherapy:

  • External beam radiation for localized symptoms or some metastases
  • Endobronchial brachytherapy, primarily to ease symptoms
  • Brachytherapy administered through the skin to treat metastases (primarily hepatic; also renal, adrenal, and lung)
  • Stereotactic ablative radiotherapy (SABR) targeting metastases

Surgery:

  • In select cases with controlled brain, adrenal, and other carefully considered metastases
  • Pleurodesis (elimination of the cavity around the lungs) for some cases with recurrent pleural fluid

Pulmonary interventions:

  • Electrosurgery or electrocautery to remove, or cryotherapy to destroy, airway obstruction
  • Stent placement to keep airway open
  • Pleural catheter placement for some cases with recurrent pleural fluid

Clinical Trials

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