Patients with metastatic NSCLC are now surviving much longer than they did 10 years ago, but these changes have not been reflected in stage III patients.— Rafael Santana-Davila, MD
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Clinicians face a number of questions in evaluating and treating patients with stage IIIA non–small cell lung cancer (NSCLC). One expert in the field, Rafael Santana-Davila, MD, reviewed key issues in managing this disease in the Journal of Oncology Practice (JOP). The ASCO Post asked Dr. Santana-Davila to summarize some of his key points. More details can be found in his JOP article.1 Dr. Santana-Davila is Assistant Professor of Medical Oncology at the University of Washington, Seattle.
Stage-Specific Controversies
Why did you choose stage IIIA, in particular, as the topic of your clinical review in JOP?
In the past decade, we’ve seen many major advances in treating stage IV NSCLC, but less so with stage III disease. Patients with metastatic disease are now surviving much longer than they did 10 years ago, but these changes have not been reflected in stage III patients. The management of stage IIIA NSCLC remains controversial, and in our article we discuss these open questions.
What do you see as the most common misunderstandings in the management of stage IIIA NSCLC?
One thing we can really improve upon is staging. We need to accurately stage every patient’s disease. This means not only doing a biopsy and a positron-emission tomography (PET) scan, but doing mediastinoscopy in patients with discrete mediastinal lymph node enlargement to verify there is N2 disease and rule out patients with stage IIIB. Sometimes, physicians do not want to submit the patient to another procedure, and they choose to skip the mediastinoscopy, but we think it is important.
The other common misunderstanding pertains to the amount of chemotherapy a patient needs. The survival of stage IIIA patients is usually poor; only 20% to 25% are long-term survivors. Sometimes, in an effort to give patients a better chance, clinicians will want to give more chemotherapy than is recommended; however, studies on consolidation treatment have shown this is not beneficial. That is why we do not recommend it unless the chosen chemotherapy backbone includes carboplatin and paclitaxel.
Role of Surgery
Is there a role for surgery in stage IIIA patients with N2 disease?
Several large trials have found no survival benefit for surgery. However, there is clearly a subset of patients who can benefit from this strategy. The problem is that it’s hard to identify them.
Our approach—and one that is shared by many cancer centers—is to offer surgery to patients if they have only one mediastinal lymph node station involved and that node is smaller than 3 cm. Again, you must accurately stage the patient, since with N3 involvement, the patient would have stage IIIB disease, and surgery would be excluded.
With local relapse after definitive chemoradiation, there is some role for salvage lung resection as well in a subset of patients. Both lobectomies and pneumonectomies are feasible, have acceptable toxicities, and can prolong survival in appropriate candidates. Ideally, these decisions are made in a multidisciplinary conference.
Optimal Chemoradiation
Is there a “best” chemotherapy regimen to use with radiation?
Concurrent chemoradiotherapy improves overall survival of patients with stage IIIA disease, but it does increase toxicity, compared with sequential chemotherapy and radiation. A number of regimens have been studied with radiation therapy, but there are few head-to-head comparisons.
Stage III Lung Cancer
Stage III Lung Cancer
- Stage III cancer is found in the lungs and in the lymph nodes in the middle of the chest (ie, locally advanced disease). Stage III disease has two subtypes:
- Stage IIIA (T1–2, N2, M0; T3, N1–2, M0; or T4, N0–2, M0): Cancer has spread only to lymph nodes on the same side of the chest where the cancer started.
- Stage IIIB (T1–3, N3, M0; or T4, N2–3, M0): Cancer has spread to the lymph nodes on the opposite side of the chest or above the collar bone.
Based on American Joint Committee on Cancer (AJCC) Cancer Staging
Manual, 7th edition, 2010.
In the United States, during radiation therapy, we mostly use cisplatin and etoposide or dose-reduced weekly carboplatin, followed by two cycles of the same agents at systemic doses. The NCCN (National Comprehensive Cancer Network®) considers several other regimens to be acceptable as well.2
Do you personally have a preferred regimen?
It is important to individualize therapy. We do this based primarily on the side-effect profile and duration of treatment that will be required. I tend to use carboplatin/paclitaxel in most of my patients, unless it would be a hardship for them to receive the additional two cycles of consolidation with this regimen.
When patients receive carboplatin/paclitaxel, consolidation at higher doses is required, but for cisplatin-containing regimens, the benefit of consolidation has not been established. While some clinicians do use consolidation with cisplatin-containing regimens, no scientific evidence suggests that it provides extra benefit; therefore, we don’t recommend it.
The choice of regimen should be based on the patient and his or her needs. There’s no cookie-cutter recipe, and there are pros and cons to all of them. For instance, we wouldn’t want to give paclitaxel to patients with preexisting neuropathy. For patients traveling a long distance for their chemotherapy, we might prefer to use a cisplatin-containing regimen, because consolidation won’t be needed.
Radiotherapy Dosing
What is the optimal radiation dose when delivering potentially curative therapy for stage IIIA disease?
Higher-than-conventional radiation doses have not been shown to improve survival. Therefore, the dose of 60 to 63 Gy in fractions of 1.8 to 2.0 Gy, established more than 30 years ago, remains the standard treatment. Higher doses should only be given in the context of a clinical trial. The same is true for proton-beam radiation therapy—it should be delivered only within a clinical trial, in my view.
A national randomized controlled trial is currently underway (RTOG 1308).3 This trial is comparing standard radiation to proton therapy, and we are enrolling patients into that study. Obviously, we need information from clinical trials to establish what the best regimens are, and we always encourage physicians and patients to consider enrolling in them.
Novel Approaches
Do targeted therapies or immunotherapies have a role in stage III disease?
These strategies are not proven yet in stage III NSCLC; however, studies are underway evaluating erlotinib (Tarceva), crizotinib (Xalkori), and other targeted agents as well as the incorporation of immune checkpoint inhibitors into the treatment schema as consolidation and even in the neoadjuvant setting. We really need to incorporate these and other new therapies into earlier stages of disease, where they are likely to influence prognosis even more than they have done in the metastatic setting.
Closing Thoughts
Do you have any final words of advice regarding the management of stage IIIA patients?
Yes. Radiologic follow-up after curative chemoradiation can detect a new primary lesion early enough for curative therapy to be delivered. In addition, with early diagnosis of disease progression, we can initiate palliative therapy earlier. Our institution and others recommend yearly chest CT (computed tomography) scans for this purpose, as no data support more intense radiologic follow-up as being associated with any improvement in survival or quality of life. ■
Disclosure: Dr. Santana-Davila has had a consulting or advisory role with Eisai, Seattle Genetics, and ARIAD Pharmaceuticals and has received institutional research funding from Lilly, Genentech, and Stemcentrx.
References
2. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Non-Small Cell Lung Cancer, version 4.2016. Available at www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed August 31, 2016.
3. RTOG Foundation: RTOG 1308 protocol information. Available at www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1308. Accessed August 31, 2016.
