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The Timeliness Factor: Duration of Work-Up for Lung Cancer
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.
Circulating Tumor Cells from Lung Cancer as a Window into the Tumor: Important Proofs of Principle Published in NEJM
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:
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?”
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:
Is Number of Positive Lymph Nodes in Resected NSCLC Important for Prognosis?
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):
Endoscopic Staging Studies for the Mediastinum
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.
(Click on figure to enlarge) Continue reading
“Occult” or “Surprise” N2 NSCLC
I was reminded of the important topic of occult N2 NSCLC by a comprehensive review that just came out in the Journal of Thoracic Oncology (abstract here) by a friend, thoracic surgeon Frank Detterbeck, who leads the thoracic oncology program at Yale. To review the basics of lymph nodes for lung cancer, N0 means no lymph nodes are involved; N1 means that lymph nodes are involved on the same side as the primary cancer and inside the confines of the lung; N2 nodes are in the middle of the chest, in the mediastinum, which is between the lungs, and on the same side as the main cancer; N3 nodes are involved and on the other side of the mediastinum or above the clavicles. Lymph nodes beyond those points are M1, or metastatic sites, and would be treated as advanced lung cancer. Occult N2 disease is also sometimes called unsuspected or surprise N2 disease as well, and it refers to a surprise upstaging of patients who were thought to have stage I or II NSCLC before surgery, but after the operation, there’s evidence that one or more mediastinal nodes are involved.
For NSCLC, one of the important aspects of staging in patients who don’t have obvious stage IV disease is staging, which is done largely based on scans, but getting tissue from mediastinal lymph nodes is a controversial central feature. However, I think the controversial nature is whether it’s definitely needed or recommended for patients who have what appears to be a stage I lung cancer (in whom the likelihood is so low it’s not definitely needed), or who have imaging that is very, very consistent with cancer in the mediastinum (in whom the likelihood is so high it’s not definitely needed). In between are many potential surgical candidates with larger stage I, or stage II, or not entirely clear but likely stage III NSCLC. In such patients, most well trained thoracic surgeons will try to get tissue with a mediastinoscopy (or other approach, like a transbronchial ultrasound or transesophageal ultrasound, both of which can sample mediastinal nodes) before surgery, because we know that outcomes are not good with surgery alone for such patients, and our standard is to give chemo or chemo/radiation before possibly proceeding with surgery. However, some surgeons don’t do mediastinoscopies, even in cases with enlarged mediastinal nodes or other features that should suggest a high index of concern (you can’t find a fever if you don’t take a temperature). You’ll never lose surgery business if you are willing to do surgery indiscriminately, on people who shouldn’t as well as should have surgery. They may feel that surgery is the most important factor, so it’s worth just pressing forward and dealing with the outcomes later. That’s below the standard of care, but that’s exactly what happens all too often, particularly when surgeons who aren’t specially trained in thoracic surgery do lung cancer resections. What is worse, sometimes during the surgery, they don’t bother going into the mediastinum to look for nodes (this can be done as a mediastinal dissection during the larger operation, if not as a separate mediastinoscopy procedure from the lower neck, going below the sternum (breastbone).
I’ll just emphasize that selection of a well trained and careful thoracic surgeon is extremely important in managing stage I – IIIA NSCLC. A poorly trained or just not motivated surgeon can do a remarkable disservice to a patient and sabotage their best opportunities for good results, and a well trained and thoughtful thoracic surgeon can maximize that. I say that as a non-surgeon. There should be a book on “When Bad Surgery Happens to Good People”. However, even if patients are treated exactly by the book by a great surgeon or oncology team, sometimes you find unsuspected mediastinal disease at the time of the full surgery, even in patients whomay have had a negative mediastinoscopy (which is a sampling, not an exhaustive search for nodes) before surgery. Continue reading
Adjuvant! Online Tool for Decisions on Value of Post-Operative Chemo
There’s a website called Adjuvant! Online, developed by oncologist Peter Ravdin, that is best known for its use after surgery for breast cancer in assessing the value of post-operative chemo. Because I don’t really treat breast cancer, I haven’t spent time on the website, but I do know that it’s a valued resource among practicing oncologists who care for patients with breast cancer. So when member NeilB gave me a heads up that there is also information now on the website that can help to estimate the value of adjuvant chemo for lung cancer, I knew it was worth checking out. I should mention, though, that the website is designed to be used by medical professionals and not directly by patients, with an intent to use the information to shape the discussion between physician or another health care provider and the patient. Still, just as I didn’t know about this tool until Neil mentioned the potential value of this website for lung cancer, other physicians could use it now based on a tip off by a patient who is interested in the analysis.
The predictions are based on some data on estimated survival based on patient age, sex, and overall health, combined with data on the T stage (based on tumor size and local areas also involved with the tumor) and nodal stage, as well as the grade of the tumor (from well-differiated to pooly differentiated, or potentially not specified). It makes a presumption about the survival advantage of platinum-based chemo after surgery, which the program estimates at a 20% relative improvement. The actual numbers on the trial are a little lower, but the support documentation about the program indicates that several of these studies used potentially inferior regimens and that 20% is an estimate based on modern cisplatin-based chemo. Importantly, it also applies to patients who have a single identifiable primary cancer, who have had surgery to stage it pathologically, who haven’t had any pre-operative treatment or any other chemo before this evaluation, and who are healthy enough to have been included on the trials. That’s not everybody, and it can’t be presumed that the program results would apply more broadly.
So you enter the variables I mention above, and based on large datasets of outcomes, it produce a set of predictions about the likelihood of
1) being cured based on surgery alone
2) being cured by chemo when they would have otherwise recurred
3) dying of recurrent cancer in the next five years, or
4) dying of causes unrelated to the cancer.
The calculator looks like this:
(Click on image to enlarge) Continue reading
Detection of Lung Cancer by a Set of Serum Biomarkers?
An interesting article just came out in the Journal of Clinical Oncology from researchers at Duke, led by Dr. Ed Patz of the Radiology Department there (abstract here). Recognizing the problems with detection of lung cancer (LC) based on symptoms (which detects LC far too late) or screening CTs (which detects early LC but also many nodules that aren’t cancer), the authors worked to develop a panel of serum proteins that can distinguish between people who have LC and those who don’t. I’ve covered the idea that one reflection of activity of a subset of LC tumors is elevation of one or more proteins, or tumor markers, in the blood (see prior post). But there is no individual marker that is reliably elevated enough in LC or normal outside of LC to serve as a useful discriminator. So the Duke group looked backwards, starting with sets of patients with and without LC (50 each) to identify a panel of proteins that were the most useful discriminators, to see if this biomarker panel that could be obtained from a blood draw could replace or, far more likely, enhance the workup of lung nodules detected based on symptoms, incidentally, or in a screening study.
Starting with a “training set” of serum from 50 patients with LC and 50 controls who didn’t have LC, they studied differences in proteins in the serum (“proteomics”) to identify four proteins that appeared to highlight differences between the groups (the individual proteins don’t matter as much as the principle), and the investigators then added two more serum markers that they believed would be relevant, carcinoembryonic antigen (CEA) and squamous cell carcinoma antigen (SCC). Measuring protein levels of these six biomarkers among the 100 samples that comprised the test set, they could come up with a model that placed every case in one of seven “bins” or patterns of activity, and with that could identify 88% of cancer patients and 82% of control patients correctly. While that’s good, that’s clearly not perfect.
They then provided an additional “test set” of another 97 serum samples, evenly split between those patients with LC and controls. Looking for the same protein patterns, or bins, the system correctly identified 71% of the patients with LC correctly, while identifying 67% of control patients. For both the training set and the validation/test set, more than half of the patients were placed into bins that allowed you to be as confident as 90-92% that LC was or was not present. So while this approach wasn’t perfect, for many patients it allowed you to be quite conflident about whether LC is or is not present.
This strategy isn’t commercially available, and it’s not reliable enough to be considered seriously as a screening test on its own. But the authors raised the point that this approach would allow for a serum-based battery of tests could very strinkingly modify the likelihood that a questionable nodule on a CT scan represents cancer not. In this way, people with ambiguous early CT findings could potentially be separated into those who you’d now feel more comfortable following radiographically and others who you’d now have a much lower threshold of obtaining tissue to clarify a diagnosis.
It’s too early for this type of approach to be recommended for general use, but this work is being studied quite actively, and I think it’s likely that in the next 3-5 years a straightforward blood test like this one will be available to help modify our decisions to move ahead with biopsy and treatment, and potentially even alter treatment decisions at some later point.
ERCC1 in Early Stage NSCLC: Likely to Become an Important Marker in the Clinic
Although I’ve described this concept in a few posts over the past year, it’s time for me to dedicate some real discussion to the concept of individualizing treatment with the ERCC1 marker. ERCC1 stands for excision repair cross-complementing group 1, and it helps repair damage to DNA. Now, validated, reliable testing for ERCC1 in tumor tissue isn’t commercially available yet to my knowledge; the company Oncotech, some of whose work I described in a prior post, has made this test available as part of their package, but I don’t think it’s validated, while other companies like Response Genetics and Genzyme are also working on a test for commercial use. The interesting thing is that ERCC1 at high levels is associated with more favorable survival after surgery and in the absence of cisplatin-based treatment. Why? Because a strong ability to repair DNA damage means that it’s possible to slow or reverse the mutation-induced problems caused by a cancer. But on the other hand, cisplatin fights cancer by inflicting damage against DNA, so expression of ERCC1 suggests that it’s easier to reverse the effects of cisplatin. And in the setting of treating patients with cisplatin-based chemo, ERCC1 expression is associated with worse survival. Looking at the results of a large post-operative chemo trial called IALT, in which half of the more than 1800 enrolled patients received adjuvant cisplatin-based chemo and half did not (abstract here), an analysis of tumor tissue from 761 patients from the IALT trial (abstract here) showed that in patients who had tumors with low ERCC1 expression by immunohistochemistry (and called ERCC1-negative, comprising 56% of those sampled), predicting a less favorable natural history (what would happen without treatment) but also an inability to repair cisplatin-induced damage, patients did significantly better with chemo vs. observation alone after surgery (median survival 56 vs. 42 months).
(Click on image to enlarge) Continue reading
Lung Nodule Growth Rate: An Important Factor in Assessing Risk of Cancer
A cancer has to grow faster than the tissue around it to become a tumor. Progressive growth is therefore a central feature of a cancer and a critical factor in distinguishing cancerous nodules from benign ones. There is a characteristic “volume doubling time” (VDT), the interval it takes for a nodule to double in volume. It’s worth keeping in mind that because a nodule is generally spherical, an increase in the diameter by just 28% (such as a 2 mm increase from 7 to 9 mm) actually represents a doubling of the volume of a nodule.
So we expect a cancer to grow, but there’s a lot of variability in the rate of an individual cancer’s growth. We know that different histologies (cancer subtype under a microscope) have different growth characteristics: SCLC has a typical VDT of 30 days, while NSCLC has an average VDT of 100 days. But on one end of the spectrum for NSCLC, a poorly differentiated adenocarcinoma or squamous cell carcinoma may have a VDT in the range of SCLC, while a well-differentiated cancer like many bronchioloalveolar carcinoma (BAC) tumors may have a VDT of more over a year. So by observing a nodule over time, we can learn a good bit about the probability of it being a cancer. For instance, nodules that grow incredibly quickly (VDT less than a week, for instance) are far more likely to be infection than cancer, and those that go for a year and a half or so without doubling are generally too slow-moving to be cancer. The common definition of stability is a lack of change over two years of observation, and then patients with a nodule being followed are generally felt to have a very low likelihood of cancer. However, I’ve seen a few cancers that didn’t have convincing growth until more than two years of follow-up had been completed (although a cancer that takes 3-4 years to double is likely to be much less life-threatening over the next several years than a more typical, faster growing lung cancer). And there’s always a rare very rapidly growing cancer that can grow remarkably during a period of observation. The key is weighing the risk of watching (which usually helps to clarify the risk that a nodule really is cancer or not) vs. the risk of jumping in and overtreating lots of nodules that aren’t cancer after all.
Among the key principles is that it’s not sufficient to just “eyeball” a nodule, but rather to have a radiologist carefully measure the nodule on a scan. And the level of detail required necessitates follow-up CT scanning rather than chest x-rays. Even with measuring nodule diameter on CT scans, very small nodules of just a few mm can differ in their apparent size just as a function of where the CT slices through the nodule (slice cuts may be every 3-5 mm for example). Imagine the difference between cutting through an orange through the middle vs. toward one side. If you only see the cross-sectional size, different cuts can give a different sense of the same nodules.
As I suggested in the discussion above about how tumor histology correlates with VDT, there have been studies that have looked at different kinds of tumors and their typical doubling times. For instance, ground glass opacities typically have the slowest VDT, with solid nodules a faster VDT, and “semi-solid nodules” in between the two (abstract here). In this study, the median VDT for pure GGOs was 813 days (as in, more than two full years), underscoring the point that some of the most indolent cancers, predominantly BACs, can grow remarkably slowly but still be a cancer (see prior post here about some of the issues with the most indolent BAC tumors).
Finally, there’s a website that includes a doubling time calculator, in which you input the dates of your CT scan studies and the size of the nodule. The calculator is here (and there’s also some more information on imaging of lung cancer).
The key points, though, are that cancers should grow over time of being observed on CT, and while there is a lot of variability in how quickly lung cancers grow, the fastest and slowest moving are less likely to be cancer than the ones that double over something in the range of a month to a year or so. The ones with convincing but not extremely rapid growth are the most suspicious for cancer.
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