October 2020 Edition Vol.11, Issue 10

Unresectable Stage III NSCLC: Guiding Patients Through Curative Intent Therapy

By Ted Bosworth


To learn more about unresectable Stage III NSCLC, click here.


Treatment in many patients with unresectable Stage III non-small cell lung cancer (NSCLC) can now be administered with curative intent – but despite the opportunity to treat with this goal, less than 50 percent of patients with Stage III NSCLC actually receive this curative intent treatment. In a podcast discussion, Robert Figlin, MD, Steven Spielberg Family Chair in Hematology-Oncology, Cedars-Sinai Medical Center, Los Angeles, CA and Victoria Villaflor, MD, Clinical Professor, Director Head and Neck Oncology, City of Hope, examined how to place more patients with unresectable Stage III NSCLC on this pathway.



Both physicians agreed the process starts with accurate staging, typically achieved through an interdisciplinary collaboration.

“Tumor boards are very important, particularly in Stage III NSCLC because it takes different types of expertise to accurately stage these patients,” said Dr. Villaflor.

By the time the tumor board meets, the discussion will be based on information already collected during the initial workup, including chest CT and PET scans to characterize the primary tumor as well as brain imaging to rule out metastases. Prior to discussion with other specialists, Dr. Villaflor said she typically performs histology on tissue samples collected with electromagnetic navigation bronchoscopy (EBUS) or mediastinoscopy.Victoria Villaflor, Thoracic Oncology at Robert H. Lurie Comprehensive Cancer Center - Medical Oncology Doctor in Chicago, IL

Based on the sampling, the board will determine, “along with the surgeon’s opinion, whether or not the tumor is resectable or unresectable,” she said.

For unresectable Stage III NSCLC, the current standard of care treatment is concurrent chemoradiation (cCRT). Administered with thoracic radiotherapy, several chemotherapy doublets are considered reasonable options for squamous and nonsquamous NSCLC in current guidelines, such as those recently issued by the National Comprehensive Cancer Network (NCCN).

In addition to the regimens most commonly used and strongly supported by clinical data, Dr. Villaflor said “there are regimens that can be used when trying to avoid specific side effects or toxicities” in relation to comorbidities or patient preferences. In some cases, cCRT might not be appropriate due to comorbidities or other factors, but this is uncommon according to Dr. Villaflor.

“I cannot remember the last time that I was not able to give a patient concurrent chemo and radiation, but there are usually preliminary steps to ensure safety,” she said.

Treating appropriate Stage III NSCLC patients with cCRT is an essential step for improving long-term survival. At the time of diagnosis, approximately one quarter of NSCLC patients have Stage III disease. Out of these patients, fewer than 20% undergo surgery. Although not all are unresectable—some decline resection—the role of accurate staging should not be underestimated for its role in directing patients to an optimal course of treatment, including one of curative intent.

The efficacy of cCRT relative to sequential chemotherapy and radiation was established in a series of trials conducted more than a decade ago, but incremental improvements have yielded substantial gains in long-term outcomes. In a recently published report, more than 30% of patients treated with cCRT were alive at five years.1

These and other data are permitting treatment with cCRT to be offered to appropriate candidates with curative intent. In physician-recommended guidelines, cCRT is characterized as a definitive initial treatment for many of the unresectable Stage III NSCLC subtypes. In most cases, adjuvant or consolidation immunotherapy, as outlined in these guidelines, is recommended. However, completion of cCRT is an essential first step.

To increase the likelihood of cCRT completion, Dr. Villaflor leads patients through a detailed discussion about the likelihood and types of potential adverse events. Over the six-week course of cCRT, the side effect burden is low initially but typically increases over time. Strategies to minimize adverse events offer a greater likelihood of completing the full course.

“When I sit with my patients, I try to get them educated upfront to ensure that the adverse events are not totally unexpected. I feel that their anxiety goes way up when unexpected things occur,” said Dr. Villaflor.

Depending on the selected regimen, such side effects as nausea and vomiting, neuropathy, and hair loss might gain significance into the second or third week, becoming more challenging over time. Some of these adverse events, whether due to the chemotherapy or to the radiation, can be prevented or substantially modified with appropriate prophylaxis and treatment.

“Many of these toxicities are not so common in today’s world because we have medications,” Dr. Villaflor said, referring to antiemetics for nausea, anticonvulsants for neuropathic pain, and other types of prophylaxis or treatment.

In the case of esophagitis, Dr. Villaflor discusses foods to avoid as well as foods less likely to induce symptoms. She emphasized the importance of ensuring adequate nutrition and intake of fluids over the full course of induction therapy to help reduce events that might delay or derail the consolidation regimen.

Dr. Villaflor stated that activity is especially important during this time “because we know from studies that patients who get more activity have less fatigue.”

One of the longer-term side effects that Dr. Villaflor worries about is pneumonitis, which is often dependent on the size of the radiation field. She also discusses with her patients less common side effects, including cardiac toxicity, hearing loss, and renal impairment. “Some of these rare side effects, such as secondary leukemia, are dependent on the drugs used in the cCRT regimen, so it is important to tailor the review of side effects for the regimen selected,” she said.

Interdisciplinary discussion of strategies to help patients manage toxicities associated with cCRT or consolidation immunotherapy is part of a comprehensive approach. When treating with curative intent, completion of recommended treatment is essential. Multiple specialists, such as nutritionists who define foods least likely to exacerbate esophagitis, or radiologists who use strategies such as intensity-modulated radiation therapy (IMRT) to improve radiation targeting, can help achieve this goal.

In the area of supportive care, proton pump inhibitors to prevent gastric acid from exacerbating esophagitis, adequate pain control to improve activities of daily living, and education about the time-limited nature of most toxicities can all play a role in successful completion of recommended treatment.

The same approach is valid for consolidated therapy, according to Dr. Villaflor. Immunotherapy typically presents a different array of adverse events, but anticipating risks is helpful. Patients informed of potential toxicities are likely to be less anxious when they occur.

“As far as the consolidated therapy, we do worry about pneumonitis, which thankfully is not super common with immuno therapy although it does happen in about 2% of patients,” Dr. Villaflor said. “We also talk about the risk of fatigue, thyroid dysfunction as well as the even rarer events that have been associated with immune consolidated therapy.”

Currently, next generation sequencing of Stage III NSCLC has the potential to reveal new information about the evolution of Stage III NSCLC and lead to personalized therapy, but sequencing has not yet altered the approach to unresectable disease, according to Dr. Villaflor.

“Most of the data so far for precision medicine has been in Stage IV NSCLC. There are clinical trials that are ongoing that are looking at different approaches in [Stage III] patients that have driver mutations, however that work is early on. It is controversial as to whether they should be treated the same or differently with targeted therapies,” Dr. Villaflor said.

According to data from the National Cancer Database (NCDB), a meaningful proportion of patients with unresectable Stage III disease do not appear to be receiving therapy with curative intent. In a report from 2017, only 23% of unresectable Stage III NSCLC patients received cCRT—defined as thoracic radiotherapy started within two weeks of chemotherapy.2

More recent data posted on the NCDB website indicate that less than 50% of patients with Stage III NSCLC are receiving curative-intent cCRT. It is likely that some of the patients are not eligible or refused cCRT, but the reasons that guideline-directed care is not being employed more frequently in unresectable Stage III NSCLC is unclear. The proportion might increase if more clinicians and patients are made aware of how current induction and consolidation therapies improve long-term survival.

Agreeing with the strategies and insights provided by Dr. Villaflor for selecting and guiding unresectable Stage III NSCLC patients to cCRT, Dr. Figlin reiterated the importance of multidisciplinary collaboration. In addition to the value of a team approach for identifying appropriate candidates for cCRT, he believes that multidisciplinary care can play an essential role in increasing the proportion of patients who complete upfront cCRT and consolidation regimens.

“It really does require a team approach,” he said.


To listen to the related podcast on unresectable Stage III NSCLC:




  1. Bradley JD, Hu C, Komaki RR, et al. Long-term results of NRG Oncology RTOG 0617: Standard- versus high-dose chemotherapy with or without cetuximab for unresectable Stage III non-small-cell lung cancer. J Clin Oncol 2020;38:706-714.
  2. Ahmed AZ, Liu Y, O’Connell K, et al. Guideline-concordant care improves overall survival for locally advanced non-small-cell lung carcinoma patients: a National Cancer Database analysis. Clin Lung Cancer 2017;18:706-718.

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