Locally advanced lung cancer

Robert Timmerman, M.D. and department Chair Hak Choy, M.D.
Department Chair Hak Choy, M.D. (right), is one of four UT Southwestern radiation oncologists who specialize in treating lung cancer. Among them is Robert Timmerman, M.D. (left), who has led research into the use of stereotactic ablative radiotherapy

Coordination, cohesion mark treatment for
middle-stage lung cancers

Treatments for locally advanced lung malignancies run the gamut of cancer care. So does the lung cancer expertise at Simmons Cancer Center.

Locally advanced lung cancer represents a heterogeneous disease requiring complex staging and treatment procedures. Although there is general agreement that patients should be treated with both local and systemic therapy, whether that entails surgery and chemotherapy, radiation and chemotherapy, or all three modalities requires detailed multidisciplinary discussion.

“We know a single treatment modality is not enough, but there is not clear consensus on which combination of surgery, chemotherapy, and radiation is best. In some cases, all three may be appropriate,” says medical oncologist Dr. David Gerber.

At UT Southwestern, where such complex cases are regularly discussed at the Thoracic Oncology Tumor Board (see multidisciplinary approach to care), interventional pulmonologists, radiation oncologists, medical oncologists, and thoracic surgeons all provide input.

Being able to identify the optimal treatments for each patient, and making that care as seamless as possible, is what makes UT Southwestern’s multidisciplinary expertise in lung cancer important, says Chair of Radiation Oncology Dr. Hak Choy. “Coordination is essential,” he says. “Here, radiation oncologists, medical oncologists, surgeons, and pulmonologists are a cohesive practice, literally under the same roof—and we work together to make decisions.”

Still, with lung cancer survival rates stubbornly low, the devil is in the details: How can radiation therapy in the locally advanced setting deliver better outcomes and with fewer side effects? Which surgical approaches offer the best chance of cure and have the fewest possible complications? And what new medicines, or new treatment combinations, may work better for these patients?

Seeking better answers

At UT Southwestern, a robust clinical trials program in lung cancer is aiming to answer such questions. It’s not just for the sake of science or for patients far in the future. People currently in treatment—including those across lung cancer stages—can benefit.

Patients in cancer trials generally receive the current standard of care, or that standard plus the experimental therapy. “Studies have shown that a person is likely to do better on a clinical trial even if the drug being tested turns out not to be effective, just because the patient is getting so much attention,” says Deputy Cancer Center Director Dr. Joan Schiller, a medical oncologist. “In a clinical trial you have a much bigger cancer care team, and they are all looking at you under a microscope, so to speak.”

UT Southwestern recently received federal funding to become a National Clinical Trials Network Lead Academic Participating Site—one of 30 hubs for clinical cancer research, especially large, multi-institution trials sponsored by national cooperative groups. “Through this program, patients receiving care at UT Southwestern will have unfettered access to high-quality clinical trials sponsored by the NCI,” says Chair of Internal Medicine Dr. David Johnson, a lung cancer clinical researcher.

Such trials are key in bringing new therapies to the clinic. “The current approach to lung cancer treatment is largely a product of well-conducted, cooperative trials, often of an intergroup nature,” Dr. Johnson says.

While clinical trials are offered by other cancer treatment centers in the community, few have the number and variety that UT Southwestern does. Most of those sites lack the depth and breadth of research that UT Southwestern offers, Dr. Schiller says. And studies involving multiple disciplines are fairly uncommon outside an academic environment, adds Dr. Choy. “They take a lot of coordination and are difficult to do.”

Maximizing synergies

But multidisciplinary studies are crucial in locally advanced lung cancer, where scientists are ever striving for improved treatment combinations.

One new strategy would incorporate immunotherapy. “When you give radiation to a cancer you may make the body’s immune system more aware of the cancer by causing the cancer to release substances in the blood that might not have been there on their own,” Dr. Gerber says.

Other efforts focus on some of the latest targeted therapies, whose potential role in locally advanced lung cancer is not clear. A study open at UT Southwestern, part of a national cooperative group trial, is testing the effectiveness of adding erlotinib or crizotinib to standard chemoradiation, depending on genetic characteristics of each patient’s tumor.

Simmons Cancer Center researchers are also leading a national trial testing a newer version of an older treatment. That study aims to see whether nab-paclitaxel, a different formulation of the chemotherapy drug paclitaxel, is more effective in a chemoradiation regimen.

Meanwhile, the integration of advanced imaging technology into radiotherapy— which allows more precise treatment delivery while better sparing normal tissue—has facilitated research into whether hypofractionated radiation can improve cancer control and survival, be more convenient for patients, and perhaps cost less. With hypofractionated radiation, the same total dose is delivered but at higher doses per treatment, with fewer visits to the radiation therapy center.

The approach is of growing interest in patients with locally advanced lung cancers who are too ill to tolerate the addition of chemotherapy, says radiation oncologist Dr. Puneeth Iyengar. A study of such patients, with stage II or III or recurrent non-small cell lung cancer, is underway at UT Southwestern. “The hypofractionated radiation may be able to overcome the loss of benefit provided by concurrent chemotherapy,” Dr. Iyengar says.

With a varied and ever-changing slate of lung cancer trials, UT Southwestern is pushing the envelope of available treatment options. Dr. Schiller urges patients and their doctors to consider a trial early in the course of cancer care.

“In clinical trials we’re introducing what we hope will be more effective treatments, and we want to introduce them early on, when someone is newly diagnosed.” That’s because the first treatment is the one that’s most important for patient outcomes, Dr. Schiller says. “A clinical trial is absolutely not a last step. It should be a first step.”

Dwight Oliver, M.D.
Experienced, specialized lung cancer pathologists such as Dwight Oliver, M.D., work with treating teams to determine the precise biology of each patient’s cancer. A cancer’s histology is critical in determining the most appropriate therapy.

Pathologists: Shining a light on lung cancer

UT Southwestern pathologists work at the cutting edge of lung cancer science for individual patients and for all patients everywhere, transforming how researchers and clinicians understand and treat the disease and providing Cancer Center physicians the most complete picture to affect a cure.

During biopsy and surgery, experienced, specialized lung cancer pathologists are onsite to ensure quality tumor tissue is acquired for analysis and to save portions for future analysis. For each case, they work with the treating team to determine the precise biology of that patient’s cancer.

A cancer’s histology is critical in determining therapy. “Knowledge of the precise histology of non-small cell lung cancer may help guide both selection—or exclusion— of therapy and may be an indicator to perform molecular testing for specific druggable targets,” notes Professor of Pathology Dr. Adi Gazdar.

Conventional drugs are more effective when used in some histological types of lung cancer—small cell lung cancer, for example—while some specific medicines are contraindicated due to serious complications in certain histologies, such as angiogenesis inhibitors in squamous carcinoma, says Associate Professor of Pathology Dr. Dwight Oliver.

In advanced lung adenocarcinoma, molecular analysis is performed because targeted therapies are now available for many of these tumors. At UT Southwestern, testing starts with preanalytic microscopic review and tumor microdissection to remove normal tissue and enrich for malignant cells, which helps to ensure a sufficient volume of cancerous cells are harvested for mutation analysis.

Molecular testing is available at UT Southwestern for any patient or physician requesting services. It is performed onsite with the latest technology, including DNA sequencing and Sequenom massspectrometry-based genotyping, which allows molecular pathologists to hunt for many more mutations with less DNA than earlier technologies.

UT Southwestern’s Molecular Diagnostics Laboratory is accredited by the College of American Pathologists (CAP) and is classified as a high-complexity lab, according
to the Clinical Laboratory Improvements Amendment of 1988 (CLIA). The Medical Center’s full-service Cytogenetics and Immunohistochemistry laboratories, directed by Dr. Prasad Koduru and Dr. Jose Torrealba, respectively, are also CAP-accredited and CLIA-certified.

As lung cancer’s molecular mysteries unfold, so does a need for new assays that can be applied in the clinic. UT Southwestern pathologists are constantly developing molecular
pathology resources and processes to ensure that newly characterized types of lung cancer are analyzed by means certifiable under CLIA.

Sometimes patients whose tumors have undergone earlier molecular testing are later referred to Simmons Cancer Center for further work. “We’re a tertiary cancer center,” Dr. Oliver says, “so often patients come here who have failed therapies on the outside, and we can do additional mutation testing, looking for targetable mutations that have not been tested for by other labs.” In all, the activity of more than a dozen genes can be examined with molecular, cytogenetic, or immunohistochemical testing at UT Southwestern, including EGFR, KRAS, BRAF, AKT, MEK, NRAS, PI3K, HER2/ERBB2, ROS1, RET, ALK, MET, and PTEN.

Joan Schiller, M.D., Deputy Director of Simmons Cancer Center.
For many patients with lung cancer, a clinical trial should be the first step—instead of a last resort, notes Joan Schiller, M.D., Deputy Director of Simmons Cancer Center. Clinical trials offer patients access to what may be more effective treatment not yet available to the general

Cancer Center pathologists might also re-examine select lung cancers after treatment. “Sometimes the patients are on these targeted therapies and their tumors become resistant,” Dr. Oliver says, “and in those cases we’ll do additional mutation analysis.”

One family’s lung cancer legacy

As a leading center for lung cancer care, UT Southwestern had all the pieces in place to discover why a 29-year-old woman with scant smoking history developed lung cancer— and to identify relatives who also were at high risk.

Cancer Center Deputy Director Dr. Joan Schiller, the patient’s physician, launched a genetic investigation after the patient mentioned in passing that she’d had two great aunts, also nonsmokers, who had died of lung cancer. The patient’s tumor revealed two mutations in the EGFR gene; blood samples showed that one, a T790M mutation that usually isn’t present in untreated tumors, was actually inherited.

Clinical Cancer Genetics Assistant Director Linda Robinson and other experts from UT Southwestern tracked down relatives, interviewed them, performed blood tests for the T790M mutation, and mapped out a family tree  that ultimately covered five generations. The team found seven relatives, including a fourth cousin, a descendant of one of the aunts, who had the mutation. Those who tested positive for it face a higher risk of developing lung cancer—even more so than heavy smokers— and are now undergoing regular lung screening with low-dose CT.

Five generations  of a family tree
Five generations of a family tree

“What we worked out for the first time was if you had this mutation you were at a greatly increased risk of lung cancer, but it was much more so if you were a never smoker and if you were a woman,” notes pathologist Dr. Gazdar, the study’s senior author.

Little research has been done into the hereditary components of lung cancer, Ms. Robinson notes, in part because the focus has been on smoking, which causes an overwhelming number of cases. “The amount of testing we did on this one family pretty much doubled in the medical literature what’s known about this gene mutation,” she says. The findings indicated about 30 percent of people with the mutation get lung cancer—and it accounts for about 1 percent of all non-small cell lung cancers.

“The big message for primary care providers is the importance of a family history,” Ms. Robinson says. “It can totally change how we manage these patients.”

Treatment Approaches

Multimodal therapy is typical, including surgery:

  • Tumor resection for cancers up to and including stage IIIA, and in some special situations IIIB cases

Chemotherapy:

  • Before, after, or along with radiation therapy
  • Before or after surgery in patients with resectable tumors

Radiotherapy:

  • In conjunction with chemotherapy
  • In patients with unresectable tumors who are not candidates for chemotherapy
  • After resection and chemotherapy in patients found to have stage III cancer at the time of surgery
  • For palliation

Clinical Trials

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