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lung cancer evaluation

The Timeliness Factor: Duration of Work-Up for Lung Cancer

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One issue that everyone with lung cancer faces, but that we haven’t covered before, is the duration of a lung cancer work-up. I’ve worked in a range of treatment settings and see patients for second opinions who come from very different backgrounds and receive their work-ups through completely different medical systems. In that process, you see some patients who receive a stunningly fast series of tests and a short interval from first suspicious finding to diagnosis and ultimate treatment of cancer. Reading the documentation of someone coming for a second opinion, it pains me a bit to see that someone was first found to have an abnormal x-ray 9 months before their diagnosis, because they were told it was likely nothing, or they were told nothing at all, only to lose 40 pounds before someone realized somthing might really be wrong. On the other hand, it’s impressive to see patients who have a brisk workup and initiate treatment rapidly. It’s certainly pretty common to have someone get a course or two of antibiotics for a few weeks after an ambiguous chest x-ray before any alarm bells go off, but how long is too long?

A couple of recent studies are now reporting some observations from different health care systems. One comes from the Veteran’s Administration (VA) system here in the US, which is the closest our country has to a single payor health care system, which lends itself to collecting a broad array of data from many institutions. The report (abstract here) describes the results from a huge chart review of 2463 patients with newly diagnosed lung cancer in around 2005 from 133 different VA hospitals. They found that there was a median of 72 days from first imaging finding to the start of treatment, with one quarter going out more than four months. There was a trend toward much shorter intervals between first imaging and treatment in patients with advanced (Stage IV) disease, at 48 days, compared with 95 and 98 days for stage I and II, respectively. Stage III patients had a median interval of 69 days before treatment started.

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Circulating Tumor Cells from Lung Cancer as a Window into the Tumor: Important Proofs of Principle Published in NEJM

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In a recent issue of the New England Journal of Medicine, a research group from Massachusetts General Hospital in Boston published some very promising results from their work showing that they can now detect circulating tumor cells (CTCs) from most patients with lung cancer and even detect EGFR mutations and other molecular findings from these cells collected just from patient blood samples (abstract here).

This new approach is based on microfluidic technology, which fortunately isn’t necessary for you to understand but basically involves having blood flow through a closed, monitored space that detects proteins on the surface of tumor cells that aren’t present on other blood cells. These proteins are called EpCAMs, for Epithelial Cell Adhesion Molecules, and with this technique, tumor cells can be detected in varying quantities from patients with blood of patients with cancer, but these cells aren’t identified in the blood of patients without cancer (abstract here). But not only can these cells be detected and the numbers monitored, but the DNA within these cells can be assessed for DNA mutations such as activating mutations that predict response to EGFR tyrosine kinase inhibitors, and even other mutations that predict resistance to EGFR inhibitors, using some novel techniques of assessing DNA from individual cells and even “free DNA” floating in the plasma.

These investigators collected blood from a few dozen patients with advanced NSCLC, many with known EGFR mutations and some with the non-mutated (“wild-type”) EGFR gene. Some had received no prior therapy, while others had received prior chemo and/or EGFR inhibitors like tarceva (erlotinib) or iressa (gefitinib). They also assessed the correlation of numbers of CTCs in a patient’s blood with the tumor burden as measured by CT scan estimates. They found that they were able to detect CTCs in every cancer patient, but that the levels didn’t correlate well with the tumor burden on imaging. They mentioned that other factors might well be important, such as the invasiveness and the vascularity (density of blood vessels) of the cancer.

Although the numbers are small, the clear majority of patients with known EGFR activating mutations from samples of their tumor also were able to the same mutation detected from CTCs (11 of 12, 92%), which worked far better than detecting the mutation in free DNA of plasma (only 4 of 12, 33%). Detection of the marker of EGFR resistance, the so-called T790M mutation, was seen in several patients who had received and progressed on EGFR inhibitors (the presence of the T790M mutation is felt to be about 50% of the patients with resistance to EGFR inhibitors – so it’s not the only mechanism of resistance). Among patients who hadn’t received a prior EGFR inhibitor but had had a T790M mutation detected (which we’d predict would be associated with no benefit from subsequent EGFR inhibitor therapy), their survival was significantly lower than that seen in the patients who didn’t have a T790M mutation:

Maheswaran NEJM T790M OS

Interestingly, some of these patients actually had a response to EGFR therapy, but they were short-lived, so they tended to have disappointing results from EGFR inhibitors even when they did respond.

A few patients were able to have their blood drawn and have the CTC levels measured over time. In contrast with the lack of correlation between tumor burden and CTC numbers in an individual patient, changing CTC levels within the same patient over time were very well correlated with responses and progression on CT imaging. And by looking at EGFR mutations over time with new techniques, the investigators saw some new mutations developing over time, not just the T790M mutation but new activating mutations sometimes as time progressed.

All of this work has been done on just a few dozen patients at a single center, so this is far from routinely available standard practice. But it’s a remarkably important demonstration for what is possible. Specifically, it’s now possible to detect and get genetic information from cancer cells collected from blood samples, and that changing numbers of these cells over time may give us information about how a patient is responding to treatment, in between or in addition to imaging results. This is particularly important because, as I had just noted in my response to nlrohde about collecting tissue from lung cancer patients, the lack of accessibility of tumor tissue from lung cancer patients is a limitation in our understanding of lung cancer, compared to the greater ability to study cancer cells from patients with leukemia, melanoma, or even breast cancer, for whom getting tissue may be an invasive procedure but doesn’t usually involve going into the chest cavity. I believe that being able to access cancer cells with a blood draw, and potentially to use these cells to monitor the status of the cancer over time, is likely to be a true breakthrough.


Removing Lymph Nodes During NSCLC Surgery: “How Does It Play in Peoria?”

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In the past couple of posts we’ve seen that based on evidence from Japan and Rome, number of lymph nodes resected and also the absolute number of positive nodes and/or proportion of positive nodes may be important prognostic variable. A third abstract I reviewed on the same subject came from Peoria, IL, and illustrated a key reason why using these variables may not be as consistently useful as we’d like, at least in many parts of the world. In the study from Japan I discussed in a recent prior post, the investigators evaluated records from 574 patients and excluded the 27 (5%) of cases in which fewer than 10 nodes were removed at surgery, because they considered this to be a suboptimal resection. Meanwhile, the study from Italy that I reviewed in my last post wasn’t as stringent but also identified 10 lymph notes as an important separation point for better vs. worse survival.

So how do we do in the US? Peoria is a town in Illinois that is considered to be so representative of Anytown, USA (at least any small to medium-sized town) that the phrase, “But how does it play in Peoria?” is a common way of asking whether something is representative of a broader American experience. As it happens, the last presentation I reviewed tells us something about these surgical questions in Peoria, because it reviewed the experience of 98 patients who underwent surgery for stage IA NSCLC at a hospital in Peoria, IL over a 7-year period (abstract here). Stage I NSCLC is defined by an absence of any lymph node involvement, so the investigators excluded the patients who didn’t have even a single lymph node removed at surgery (not exactly a high bar compared with the experience in Japan, where they excluded the 5% of cases where fewer than 10 nodes were removed! (And we don’t even know how many cases in Peoria missed that rather non-ambitious cutoff…) They found that, as in the Italian study, prognosis was better in the patients in whom more lymph nodes were removed, as shown here:

Peoria LN experience

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Is Number of Positive Lymph Nodes in Resected NSCLC Important for Prognosis?

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At this year’s ASCO meeting, I had the opportunity to review and provide commentary on several presentations from other researchers, all on the topic of how to refine our ability to predict how patients will do after surgery for stage I – IIIA NSCLC, with an idea that this information can help guide decisions about who should receive chemo and who shouldn’t.

One of the interesting abstracts came out of Japan, where a group of investigators led by Dr. Matsuguma looked details about the surgical results and long-term outcomes of 574 patients who all underwent surgery at a single center, asking the question of whether the number of lymph nodes involved with cancer is important for prognosis, and specifically whether this variable might be more important than the location of the lymph nodes in its correlation with prognosis (abstract here). Our current system of assigning node stage is based not on number of lymph nodes but rather where any nodes with cancer happen to be. Lymph nodes in the same lung as the cancer are called N1, while nodes outside of the lung and in the middle of the chest are designated as N2 on the same side of the chest as the main cancer, or N3 on the opposite side. Lymph nodes above the clavicle are also considered N3. This staging from N1 to N2 to N3 is somewhat associated with worse prognosis, primarily because involved nodes further from the cancer are associated with a greater risk of spread of the cancer to distant parts of the body. A lung cancer generally needs to have some ability to spread to get out to N2 or N3 nodes, and that’s associated with a higher likelihood of recurrence outside of the local area of the chest.

The group recognized that at the time of surgery it can be hard to know which nodes came from what exact area, and also that sometimes we see “skip nodal metastases” in which N2 or N3 nodes are involved without any N1 nodes involved, which you wouldn’t expect to happen with a stepwise escalation of aggressiveness. They also thought it might matter whether one lymph node is involved or multiple nodes is involved in a given location. So they looked at the question of whether you could do a better job with the current system that uses nodal location by also adding information about how many nodes were involved. And they found that compared with the current system (left side of the figure below, with little separation of the N1 vs. N2 groups, so not great at offering prognostic information), adding information about the number of either N1 nodes involved (4 or fewer vs. more than 4; upper curve on right) or N2 nodes involved (6 or fewer vs. more than 6; lower curve on right) could help stratify the prognosis for both groups, providing a clear separation of a better and a worse subgroup):

Number of Nodes Involved and Px

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Endoscopic Staging Studies for the Mediastinum

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I’ve described mediastinoscopy as a “gold standard” preoperative procedure in patients who are candidates for surgery. Although it’s controversial whether patients with a very low likelihood or a very high likelihood of cancer in the mediastinal nodes (mid-chest, between the lungs) need to have this confirmed by obtaining tissue to review under a microscope, we strongly prefer to get tissue for patients in whom this is a reasonably open question. For patients who are good surgery candidates and in whom there is no evidence of cancer in the lymph nodes of the mediastinum, surgery is the preferred next step. For patients who are good surgery candidates but have lymph node involvement confirmed on the same side as the main cancer (N2 nodal involvement), we most commonly recommend chemo and sometimes radiation before pursuing surgery, or recommend chemo and radiation without surgery. And for patients who have cancer in the mediastinal lymph nodes on the side opposite the main tumor (N3 nodal disease), we generally recommend chemo and radiation rather than a surgical approach. Why the difference in management? Because as nodal stage increases, the risk of cancer recurrence outside of the chest becomes greater, meaning that we need to think about distant disease (and chemo to cover it) more and more, because even excellent local treatments like surgery or radiation, or both, just can’t address micrometastatic disease outside of the treatment area.

While the gold standard has been mediastinoscopy, it’s invasive and requires general anesthesia. Serious complications are rare, but it’s not a trivial procedure either. And it’s very difficult to do a repeat mediastinoscopy to assess response to induction (pre-operative) chemo or chemo/radiation if a prior mediastinoscopy was done for initial staging. So having another option for getting tissue from mediastinal lymph nodes, especially if it is minimally invasive, would be very welcome.

One of these options that is gaining traction uses endoscopy, a tiny camera on the end of a tube, which can be used to look down the esophagus at the stomach (“upper endoscopy” or EGD, for esophagogastroduodenography), or the bronchial tree of the lungs (bronchoscopy). These procedures usually just require sedation, don’t require any incisions, and don’t leave visible scars. An endoscope can have an ultrasound probe attached to it so that a trained physician can get an idea of the shape and size of things behind visible barriers, allowing them to find enlarged lymph nodes that may be behind the walls of the esophagus or bronchi. The endoscope also includes a needle that can be injected into a suspicious node or tumor within the bronchus.

EBUS fig

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