Before considering various treatment options, of course one has to complete the diagnostic and staging workup. I make sure that the slides are reviewed carefully by a pathologist at our institution to ensure that the diagnosis is correct and that the histological subtype of NSCLC is identified.
I would seriously consider getting a core biopsy to be certain that we are not making a diagnosis based on a few scattered cells from a needle aspirate.
I do not order fluorodexoy glucose (FDG) positron emission tomography (PET) if a patient has a clear-cut evidence of metastatic disease in other sites. I would get a baseline MRI of the brain even if patients do not have any symptoms of brain metastasis, particularly when bevacizumab is being considered as a part of therapy.
Enroll Patients in Clinical Trials!
Before we discuss the treatment further, I feel compelled to highlight once again the importance of enrolling patients in clinical trials. It is tragic that only 3% of adult patients with cancer in the United States, arguably the country with the best cancer care in the world, are enrolled in clinical trials. Unfortunately, even in major cancer centers, only 15% of patients with lung cancer are enrolled in clinical trials.
EGFR TK Mutation Tests for Everyone?
Should we send the biopsy samples from every patient with metastatic NSCLC for epidermal growth factor tyrosine kinase (EGFR TK) mutation testing today? If you think use of erlotinib should be restricted only to patients with metastatic NSCLC who have EGFR TK mutations (much like trastuzumab for HER2-positive breast cancer), I believe you should then screen every patient with metastatic NSCLC. Occasionally even a male heavy smoker may have EGFR TK mutation.
On the other hand, if you feel (like me) that the knowledge of EGFR TK mutation testing only helps you to select the timing of treatment with erlotinib (in the frontline setting or preferentially over other agents in the maintenance setting as opposed to second or third line), I believe you could be selective in screening patients for EGFR TK mutations. It will then be a patient who is a life-long never-smoker or a very light smoker who quit smoking decades ago.
This is certainly an area of controversy and a good topic for robust discussion in the blog version of this article (http://bit.ly/OTBlog-HowDoITreat-MetNSCLC) — please add your comments!
I do not believe we have enough data to effectively use other markers such as K-ras, ERCC 1, or RRM1 in routine practice (outside of the context of clinical trials).
I am certain that we will be ordering a panel of biomarkers to select patients for appropriate therapy in the near future.
Frontline Therapy—Performance Status, Histological Subtype, Co-morbidities
I take into consideration performance status, histological subtype, and of course, the presence or absence of co-morbidities to choose appropriate treatment for patients with newly diagnosed metastatic NSCLC.
Let me first address my approach to those with a good performance status and non-squamous NSCLC. I treat patients with NSCLC whose tumors exhibit mutations in the EGFR TK with single-agent erlotinib until disease progression. I do not combine chemotherapy or bevacizumab in combination with erlotinib.
If patients are known to have wild-type EGFR TK or when the EGFR TK mutation status is not known, I would treat them with platinum-based doublet chemotherapy.
The choice of chemotherapy regimen varies, of course, depending on the histological subtype (squamous vs non-squamous NSCLC) and on whether the patients would be candidates for bevacizumab.
I would add bevacizumab to a platinum-based doublet therapy (typically paclitaxel, carboplatin, and bevacizumab—the ECOG 4599 regimen) when treating patients with metastatic nonsquamous NSCLC who have no history of hemoptysis, bleeding, or recent ischemic vascular events.
For those with non-squamous NSCLC who are not candidates for bevacizumab, I prefer to use pemetrexed and carboplatin. Even though the study that led to the approval of pemetrexed in the frontline therapy was conducted using cisplatin, I do feel that carboplatin is appropriate for patients with metastatic NSCLC. I try to use cisplatin in potentially curative situations (adjuvant therapy, locally advanced NSCLC) whenever possible.
I treat patients with squamous-cell NSCLC with either paclitaxel and carboplatin or gemcitabine and carboplatin for induction therapy.
Maintenance Therapy—Not for All!
After four cycles of therapy, I would continue maintenance therapy with bevacizumab as was done in the ECOG 4599 study if patients received a bevacizumab-containing chemotherapy regimen in the frontline setting.
After four cycles of therapy if patients have stable disease, I generally continue pemetrexed (for those with non-squamous NSCLC who did not receive bevacizumab in the frontline) even though most of the maintenance studies have “switched therapy” to a different agent other than the one used in the frontline setting. While I can legitimately be criticized here, the excellent tolerability of pemetrexed, in my humble opinion, justifies this transgression away from evidence-based medicine (at least for now) unless the results from an ongoing study testing the role of maintenance pemetrexed in patients who have received pemetrexed-based induction regimen fail to support this practice.
I have generally not offered any maintenance therapy for patients with squamous cell NSCLC. I do think docetaxel produces more fatigue and cumulative toxicities than drugs like pemetrexed (not an option for patients with squamous NSCLC) or erlotinib, and so save them for the inevitable progressive disease.
Erlotinib is certainly an option to consider here based on the recent results of the SATURN study (and for non-squamous NSCLC as well).
Of course, maintenance therapy is not for everyone. I do present both options to patients—maintenance therapy and close observation and a break from chemotherapy. I do have to concede that when I see a patient with excellent performance status who has stable disease after four cycles of induction therapy, my discussion tends to be biased gently in favor of maintenance therapy.
Elderly and Poor Performance Status
As for elderly patients, I make my decision based more on the performance status and the presence or absence of co-morbidities than by mere chronological age, with one possible exception: I tend to be even more selective for bevacizumab in patients over age 70, especially if there is a history of recent ischemic vascular disease.
I generally use only single-agent chemotherapy for patients with a performance status of 2—pemetrexed for those with non-squamous NSCLC and vinorelbine for those with squamous-cell NSCLC.
Last But Not Least
I follow patients with metastatic NSCLC who are being treated with systemic therapy with serial computed tomography (CT) scans and not with FDG PET scans. It is important not to over-interpret changes in the standardized unit uptake (SUV) on FDG PET scans as they are influenced by factors other than disease progression. It is also worth keeping in mind that almost all the large practice-changing studies have used CT scans rather than CT-PET or PET scans.
We are very happy to announce this new series edited by Dr. Govindan.
He kicks off the series with this first article, and for future ones he has asked other thought leaders to tell how they would approach the treatment of a patient in their area of expertise.
These pieces will be written in a conversational, colleague-to-colleague style. As Dr. Govindan notes, “While all of us want to see more patients enrolled in well-designed clinical trials, this series will be all about how one treats patients “off-protocol” in routine clinical practice. Practice patterns vary, since we do not always have firm data for every single clinical scenario.”
Please let us know what you think! Add your comments in the blog version of the series — http://bit.ly/OTHowDoITreat — both about individual treatment scenarios as well as to suggest future questions.