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Surgery for Small Cell Lung Cancer?
One topic that is rarely considered in the management of SCLC is the role of surgery. The main reason is that the vast majority of patients presenting with SCLC either have extensive disease that has spread throughout the body (2/3 of SCLC presentations) or at least already have rather bulky nodal disease that would make then a less-than-ideal candidate for surgery even if they had NSCLC; the other key component of this bias against surgery is the strong tendency for SCLC to have micrometastatic disease even early in the disease process. That’s why chemo has long been the cornerstone of treatment, even for limited/localized disease, where we have traditionally added chest radiation to chemo in order to provide local disease control.
The estimate is that approximately 5% of patients with SCLC present with “early stage” disease that doesn’t even involve mediastinal (N2) lymph nodes, in the middle of the chest and outside of the lung, but on the same side as the main tumor (abstract here). Even so, most cases of resected SCLC arise from cases in which a small “coin” lesion in the lung that wasn’t suspected to be SCLC is removed either without a preceding biopsy or after a biopsy that didn’t show SCLC – either by being non-diagnostic and suspicious for cancer or showing NSCLC on the limited biopsy but actually being a “mixed” tumor with some elements of SCLC and other elements of NSCLC. This situation of a mixed SCLC/NSCLC tumor is quite uncommon but not rare, and it is conventionally treated as SCLC. So most resected SCLC cases I’ve encountered and heard of from others have been unsuspected SCLC. But should surgery have a role for the small minority of patients with early stage SCLC?
Nexavar (Sorafenib) as Late Therapy for Advanced NSCLC: Does This Drug Have Activity?
We’ve been following sorafenib (nexavar), a multi-kinase inhibitor with anti-angiogenic activity (see prior post). This oral agent, which is already approved as an effective treatment for cancers of the liver and kidney. It’s been studied as a single agent and appears to perhaps be associated with prolonged stable disease even if not with clear tumor shrinkage, but a randomized phase III trial of chemo with or without sorafenib showed no benefit and a particular lack of benefit (actually, an increase in mortality, as in risk of death) in patients with squamous NSCLC (see prior post).
Another study was presented at ASCO this year by Dr. Joan Schiller, now at Univ. of Texas – Southwestern in Dallas. She heads the lung committee for Eastern Cooperative Oncology Group, or ECOG, one of the main North American collaborative cancer research groups, which ran this multi-center trial, known as ECOG 2501 (or E2501)(abstract here).
This trial had a very novel design, which was used specifically to study an agent that may be beneficial primarily for lung cancer patients with slowly growing disease, if sorafenib is indeed an agent that slows progression more than shrinks tumors dramatically. The study used what is called a randomized discontinuation design, in which all patients started by receiving sorafenib for two months, and those with a response (very few) continued on sorafenib, while those who progressed in that time came off of the study. But the patients who showed stable disease after two months on the trial were then randomized to continue on sorafenib or go onto a placebo. The trial design looks like this:
Longterm Survival with Iressa in BAC
One of my earliest posts when I started OncTalk was on the use of oral inhibitors of the epidermal growth factor receptor (EGFR), one of the growth signals that is often over-active in cancer cells, against advanced bronchioloalveolar carcinoma (BAC), a unique subtype of lung cancer that tends to grow within the lungs, sometimes slowly, and not progress elsewhere. These EGFR inhbitors like iressa (gefitinib) and tarceva (erlotinib) have certainly been well studied in NSCLC in general, but both of these drugs have been a focus of particular attention as a treatment for BAC. In fact, the largest trial that has yet been conducted in advanced BAC is one that I led, called SWOG 0126, that gave iressa at 500 mg by mouth daily (actually twice the dose that was eventually settled on, but possibly a more effective dose) to 135 eligible patients with advanced BAC. My colleagues and I published the results of this trial a couple of years ago (abstract here), but this year at ASCO I presented the results with longer-term follow up (abstract here), which yielded some interesting findings.
Obviously, the response rates and side effects didn’t change with a couple of years of longer-term follow up. Nor did the median progression-free and overall survival numbers, since those reflect the point at which half of the patients will have demonstrated progression or have died:
It’s worth noting that while this study enrolled both patients who had never been previously treated and some other patients who had received prior chemotherapy, both the chemo-naive and previously treated patients had the same progression-free and overall survival results, as shown in the superimposed curves shown above.
Amrubicin in Relapsed SCLC: Continued Momentum at ASCO
Last year, I had the occasion in two prior posts (here and here) to highlight a new agent called amrubicin that is being studied in relapsed SCLC. At an ASCO conference where most of the news in SCLC was disappointing, amrubin studies again appeared promising.
The first of these studies was reported by Dr. David Ettinger at Johns Hopkins University (abstract here). This trial enrolled 75 patients who all had refractory disease, meaning that they had shown progression within 90 days of completing first line chemo) to receive amrubicin at 40 mg/m2 IV on days 1-3 every 21 days. In fact, the median time of being off chemo was only 38 days before starting amrubicin, which is associated with what we’d expect to be a low probability of benefiting much from more chemo. The response rate in the trial was 17.4%, well below the impressive response rates in the 50% range seen in Japan (where amrubicin is commercially available now, I believe), but in this setting of refractory patients, any responses are seen as pretty encouraging. The median progression-free survival was 3 months. Side effects were not a significant problem, with 62% of patients experiencing moderate to severe neutropenia (decreased white blood cell counts), a very common side effect of chemotherapy, and no significant heart toxicity, which has been a concern about this class of chemotherapy drugs (called anthracyclines).
Tarceva (Erlotinib) in the Elderly
One of the initial appeals of targeted therapies like tarceva (erlotinib) was that they may have fewer side effects and emerge as an alternative to standard chemo for some people. And one of the most appealing areas for offering a good alternative to standard chemo has been in the setting of older patients, who may be more wary of side effects and/or have additional medical problems than younger patients.
A theme that has emerged very consistently in studies of elderly patients in lung cancer, and largely in oncology in general, is that fit older patients without many medical problems are very likely to do every bit as well as younger patients. Although studies of older patients with lung cancer have largely paired the elderly and “poor risk”/frailer patients (performance status of 2, corresponding to being symptomatic, a little limited in activities, but spending more than half of the day in bed or a chair) in pooled trials. More recently, though, we’ve come to recognize that these are overlapping but definititely distinct groups. We also learned in a prior post that unselected patients (not singled out by things like having never smoked, or having an EGFR mutation, for instance), with a marginal performance status who receive tarceva instead of standard chemo clearly do less well than patients who get standard chemo. But how well do older patients do with tarceva, independent of performance status? This is an important question now that more than half of all newly diagnosed lung cancer patients are over 70. A couple of trials help shape our thinking here.
Concerns About Surgery for Lung Cancer in the US: A Hard Look in the Mirror
As a conclusion to the string of posts on the topic of lymph nodes removed at the time of surgery, I wanted to touch on the issue of what our representative experience is in the US, because I described the results of specialized centers in Japan and Italy that typically yielded large numbers of lymph nodes, often more than 10. What is the US lung surgery experience?
Perhaps the best answer we can get is from a seminal paper by Dr. Alex Little and colleagues that was published in 2005 in the Annals of Thoracic Surgery (abstract here). This describes the results of a survey done of 729 US-based hospitals (all over), some academic but mostly community-based, of surgeries from 11,668 patients with lung cancer, nearly 60% of whom had stage I disease, and most of the rest with stage II or III NSCLC, and 6% stage IV (this could include surgery with curative or palliative intent, and likely included many patients suspected as being earlier stage prior to surgery). Consistent with the demographics of lung cancer today, 46.8% of patients who underwent surgery were 70 or older, and 9.5% were 80 or older. Surgeons clearly were willing to treat at least a subset of elderly NSCLC patients aggressively.
One of the most discussed findings since the paper was published is that only 27% of patients with NSCLC underwent a pre-operative mediastinoscopy, which is something that most specialty-trained thoracic surgeons recommend for all but the lowest risk patients for mediastinal node involvement (such as a nodule less than a cm or two, particularly squamous (less likely to spread early), and maybe with a negative PET scan. But at my center, for instance, the very well trained lung surgeons do a mediastinoscopy on the vast majority of lung cancer patients, because it’s not that uncommon to find unsuspected nodal involvement at a mediastinoscopy, even in patients who had a PET scan that appeared negative (no suggestion of uptake consistent with cancer in the mediastinum).
Another major issue was that of the patients who did undergo a pre-operative mediastinoscopy, less than half (46.8%) had even a single lymph node removed at that time. Taking a look but not doing a biopsy of a single node, let alone the several that are considered a requirement for a proper medistinoscopy, is really tantamount to not doing the procedure at all. And even at the time of surgery, only 57.8% had any lymph nodes removed from the mediastinum. So more than 40% of patients had a clearly inadequate pathologic staging, at least from the perspective of nearly all leading surgical experts.
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:
Importance of Number of Lymph Nodes Removed at NSCLC Surgery
In the last post I discussed some interesting work from a group in Japan that suggested that the number of lymph nodes that are removed and positive for NSCLC may be a very important prognostic variable, potentially an even more important factor than location of the nodes, which is the basis for how we stage nodal involvement in NSCLC now. Following along the same theme was another interesting presentation I reviewed at the recent ASCO meeting that came from Rome, where investigators at the Regina Elena National Cancer Institute reviewed the detailed results of 415 consecutive patients who underwent surgery there for stage I to stage IIIA NSCLC (abstract here). They attempted to assess the prognostic value of many variables reported to be useful in prior work, such as age, patient sex, tumor size, tumor grade, and also focused on the variables of the total lymph nodes removed at the time of surgery (regardless of whether they were involved with cancer or not), and the proportion of positive nodes compared with the total number removed (related to the concept in the previously described Japanese abstract about the number of positive nodes as a number alone). From there, they also developed a new system of weighted variables that could assign patients as low, intermediate, or high risk of recurrence and death from lung cancer after surgery.
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):
Alimta Disappointing in Small Cell Lung Cancer (SCLC)
As described in my last post, one of the interesting points we’ve seen from the recent trial of maintenance alimta vs. placebo after first line chemo for advanced NSCLC is that alimta’s beneficial effects appear to be concentrated on the 2/3 of patients with non-squamous cancers, while the patients with squamous cell NSCLC did no better with alimta than with placebo. That post also described how sensitivity to alimta may be associated with low levels of a relevant target enzyme for alimta, called thymydylate synthetase (TS), and that TS levels are relatively high in squamous cell NSCLC, and also in SCLC.
Unfortunately, the results of a large trial in extensive SCLC (abstract not yet available on ASCO website) clearly confirmed that alimta isn’t an improvement as a treatment for SCLC. This trial was designed to directly compare the regimen of carboplatin/alimta to carboplatin/etoposide, which is a standard regimen for this setting. It was designed to enroll 1820 patients (!) and look for a significant improvement in survival. The study had enrolled 733 patients when the “Data Safety Monitoring Board”, which reviews results during the conduct of a trial to ensure that one arm isn’t doing so remarkably well or poorly that it would be unethical to continue to randomize patients, found that the carbo/alimta arm was doing so poorly that it was not possible that it would ever emerge as superior. It was closed, and Dr. Socinski presented the results.
In pretty much every measure, the carbo/alimta arm fared worse than the arm receiving standard carbo/etoposide. Median progression-free survival was 3.7 vs. 5.3 months, and the survival curve shows the dramatic difference:
The other measures supported the same conclusion. The median overall survivals with carbo/alimta vs. carbo/etoposide were 7.3 vs. 9.6 months, and response rates were 25% vs. 40%. Even side effects, usually a very strong suit for an alimta regimen, didn’t look better than carbo/etoposide, and in some measures like degree of anemia and need for transfusions, the carbo/alimta regimen was significantly worse.
There isn’t too much more to say about it, except that it was remarkably convincing that there was nothing to recommend alimta in the setting of SCLC. It certainly deserved to be tested, and this regimen had looked promising in smaller earlier trials in SCLC, but it was one of the most definitive answers you could ever see. While we’ve become quite impressed with its value in NSCLC, and from now on perhaps particularly in those patients with non-squamous cancers, I would say that alimta doesn’t have much of a future in SCLC. On the other hand, the results looked favorable enough for the regimen of carbo/etoposide, which is reassuring to see when we’d like to consider it as a kinder, gentler alternative to cisplatin/etoposide for ED-SCLC. So perhaps there was still some positive that came out of this otherwise disappointing trial.
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