Emerging Modalities Abound in Stage III NSCLC Treatment

William T. Sause, MD

Treatment for patients with stage III non—small cell lung cancer (NSCLC) has significantly evolved over the past few decades to include better patient selection as well as chemoradiation, immunotherapy, and other modalities—all of which require further research, explained William T. Sause, MD.

“Even though the tools have changed, the scientific discipline to study the tools and analyze your outcomes has not changed. I would focus on the process of evaluating new agents [in future treatment approaches],” said Sause, a radiation oncologist at Intermountain Healthcare.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Sause discussed various modalities of stage III NSCLC treatment and how to effectively select patients for the varying regimens.

OncLive: How has the management of stage III NSCLC changed over the years?

Sause: The biggest change has been in the selection of patients for aggressive therapy versus nonaggressive therapy. We've developed a pretty good realization of what it takes to tolerate aggressive combination therapy. When we incorporate chemotherapy with radiation, it's quite difficult and toxic. If you select your patients appropriately, it's quite efficacious; however, if you select your patients poorly and they are unable to tolerate the treatment, it doesn't work very well and causes a lot of harm.

One of the big improvements we've made over the last several decades has been selecting our patients better—both anatomically and physiologically. The next big change has been the incorporation of immunotherapy.

Stage III disease is a challenging disease. Some stage III patients are surgical candidates, and if they are, then surgery is probably appropriate. Some stage III patients are candidates for systemic therapy alone. It's extremely variable and idiosyncratic to the individual patient. It's almost impossible to put it into a little box with instructions on how to treat patients at each stage. In fact, when you poll cancer centers across the country and ask them if surgery is appropriate in stage III disease, half of them say no, and half of them say yes.

How has patient selection for NSCLC treatment improved?

Many of the trials that we conducted during the 1980s were negative trials. They showed no benefit to combining chemotherapy and radiation. As we moved into the 1990s, we began to more appropriately select patients for this treatment, including those who could tolerate chemotherapy well and did not have advanced anatomic disease. When we were able to select patients based on performance and physiology, patients did dramatically better on a chemotherapy and radiation combination.

What factors are considered when choosing treatment for patients with NSCLC?

Patients in the anatomic stage of the disease, even though they may have palpable nodes, were excluded from our combined trials. These patients included those with advanced stage III disease, those with poor pulmonary function or advanced mediastinal disease that made radiation difficult, or patients with poor performance status or a greater than 10% weight loss. Those patients did not tolerate systemic therapy very well, and when we eliminated them from the protocols, we were able to see a benefit.

How is chemoradiation used to treat patients stage III NSCLC?

The backbone of combined therapy has been the use of cisplatin; the incorporation of cisplatin with concurrent radiation has been a dramatic improvement. When we look at other doublets of chemotherapy, including gemcitabine and taxanes, there is no dramatic difference between the different regimens, at least in stage IV disease. In stage III disease, when we're using the drugs as a radiosensitizer, then there will likely be a definite path after using cisplatin. Cisplatin is not an easy drug to tolerate, particularly in the elderly. We're always looking at ways to make [cisplatin] better tolerated and find alternatives.

What are the arguments for surgical versus nonsurgical approaches?

The argument against surgery is that it's morbid and patients could die of systemic disease anyway. Therefore, why put them through surgery? The argument for surgery is that it is the most effective tool we have to get rid of the cancer. Although there may be some increased morbidity and adverse events, it's worth undergoing if you can get rid of all the cancer.

There is one clinical trial that randomized patients with stage III NSCLC to surgery or no surgery, and there was no difference between surgery and nonsurgical treatment. If we're going to select patients for surgery, it needs to be a very disciplined process.

How is immunotherapy now used to treat this patient population?

Immunotherapy has made a dramatic improvement in [many] patients with lung cancer. The molecular targeted agents have also been exceptionally beneficial. However, the reality is that only a small number of patients are candidates for a molecularly targeted agent, whereas [there are more candidates] for immunotherapy. It has made a dramatic change in how we treat these patients.

Much of the [future] research is going to be on identifying newer molecular targets and fine-tuning our use of immunotherapy. We use PD-1 inhibitors, but it's obvious that there is a cascade of checkpoint inhibitors. I'm sure there will be new agents in the future that will augment those checkpoint inhibitors and make immunotherapy more successful.

What other emerging modalities are you excited about?

I treat a lot of patients with localized lung cancer. For them, we use stereotactic radiosurgery, which has been an improvement over surgical resection, particularly in elderly patients with comorbidities who you don't want to put through an operation. The use of stereotactic radiation to those peripheral stage I tumors has been fantastic, and has resulted in as many cures as surgery with less morbidity. Unlike the past when those patients would not have been treated just at home, we have something to offer them that is curative.