This is the first in a series of “uncut” videos that I’m starting that will focus on illustrative cases from my clinic that highlight some broader teaching points. This particular video is on the decision-making process that led me to recommend adjuvant chemotherapy for a patient who underwent surgery for a 3.5 cm lung adenocarcinoma without lymph node involvement. Though this size is under the threshold we often use for recommending post-operative chemo, which is 4 cm, her particular cancer had some other features that made me concerned it may represent a high enough risk to favor additional treatment, in combination with her overall good health and desire to pursue a more aggressive approach if there is a good rationale for it.
As always, I’d welcome your thoughts, questions, objections, etc., as well as any feedback you want to offer about the format of using clinical cases to review broader concepts. And any ideas for topics are also welcome.
The next live webinar to be done through the partnership of GRACE and LUNGevity Foundation will be on the timely subject of using molecular features of a resected non-small cell lung cancer in order to better understand the probability of the cancer recurring. This will be on November 14th, 7 PM Eastern/4 PM Pacific, and will hope to answer the question, “Could these molecular features improve upon current staging efforts to help us refine our recommendations of which patients should receive post-operative chemotherapy in order to reduce the chance of recurrence?”
To help us answer that question, we’ll be joined by Dr. Johannes Kratz, surgeon at Massachusetts General Hospital in Boston, who participated in important research while previously at the University of California in San Francisco on a molecular profile that can be performed on archived tissue (stored in wax after completion of the surgery) and has demonstrated an ability to discriminate between patients with a better or worse prognosis after surgery. This research was published in the prestigious journal The Lancet (with Dr. Kratz as lead author), was highlighted in one of my posts at the beginning of this year as an exciting new development, and this testing platform has recently become commercially available.
Dr. Kratz will review various efforts pursued to use tumor biology to refine treatment recommendations in patients with early stage NSCLC, including the benefits and limitations of different strategies. He will discuss ongoing research and current standards of care in this clinical setting.
We’ve covered the potential value of systemic therapy for early stage NSCLC in a wide range of posts and podcasts, and to summarize what we’ve learned in a sentence, it’s basically that chemotherapy can significantly increase progression-free survival (PFS) and overall survival (OS) in patients who have undergone curative surgery for stage I-III NSCLC, but the benefit is far more convincing in patients with a high enough risk to justify the potential adverse effects of chemotherapy. In fact, in patients with node-negative cancers that are smaller than about 4 cm, the evidence isn’t very good that chemotherapy improves outcomes, and there is a strong suggestion from the limited available evidence that it may be net harmful. This makes sense to me: chemotherapy represents a fixed negative effect (both quality of life and risk of adverse effects) whether a patient has a high risk of recurrence or a low risk of recurrence and can reduce the chance of the cancer recurring by a certain proportion. If the risk of recurrence is high (such as in someone with stage II or III resected NSCLC), chemo can reduce that risk quite a bit, so the net effect is very positive: big anticipated benefit exceeds small risk. However, in patients with smaller node-negative cancers, the magnitude of benefit is going to be very low because the risk of recurrence is too low for the chemo to have much absolute effect: small risk exceeds even smaller anticipated benefit.
In recent years, we have generally focused on post-operative, or adjuvant chemotherapy, because the majority of positive trials for early stage patients have used an adjuvant strategy. However, going back in time ten years, both pre-operative (neoadjuvant) and post-operative chemotherapy were investigational approaches, and they each have their advantages and disadvantages. Post-operative chemotherapy has the benefit of being able to make treatment recommendations based on the most accurate staging information (from surgery) and provides the opportunity to do the most pivotal treatment immediately, but many patients are simply not able to consider chemotherapy within the first couple of months after surgery, and/or they need to abort treatment before the intended therapy has been delivered. Pre-operative chemotherapy provides the earliest opportunity to treat potential micrometastic disease, should improve the probability that treatment will be delivered as planned (because few people will decide to abandon surgery), and it gives the chance to get feedback on how effectively the systemic therapy shrunk the cancer. However, it also entails a small but real chance that the person’s cancer will grow and even potentially no longer be able to be resected, and possibly that chemo could increase the risk of surgical and post-surgical complications. Pre-operative therapy may also have an advantage of allowing a patient to receive a less extensive surgery after a good response to initial systemic treatment.
So it’s fair to say that there is a good rationale to test both of these strategies, and studies have been pursued with surgery followed by randomization to chemo or observation, immediate randomization to chemotherapy followed by surgery or immediate surgery alone, and even one trial that randomized patients to pre-operative chemotherapy followed by surgery, surgery followed by chemotherapy, or neither pre-operative nor post-operative therapy and just surgery alone. By 2003 and 2004, several trials of post-operative chemotherapy were reported as positive, and this led to early closure of several of the important pre-operative chemotherapy trials, since the emerging picture was that chemotherapy provided a benefit that made randomization of patients to a surgery alone arm unethical.
It is in this context that we can now review the significance of the newly published Chemotherapy in Early Stages Trial (ChEST), which was conducted at 45 centers in 15 countries in Europe and attempted to assess the benefit of three cycles of cisplatin/gemcitabine before surgery, compared with surgery alone. The trial was designed with an intent to enroll 712 patients with stage IB to stage IIIA NSCLC (stage IIIA only if they had no mediastinal nodal involvement, so T3N1) and was looking to detect a 20% improvement in PFS as the primary endpoint, but from 2000 to 2004 only 270 patients were enrolled (129 randomized to pre-op chemotherapy, and 141 randomized to surgery alone). It closed early in light of the mounting evidence supporting a role for chemotherapy. Continue reading
The answer is, “Usually pretty early”. I tell my patients that the risk is “front-loaded”, meaning that we typically see recurrences occur in the first couple of years after curative therapy for lung cancer, if they’re going to happen at all. That said, I haven’t seen a lot of data that actually illustrates the point, but there was a presentation at ASCO this past year that addressed how well recurrences/disease-free survival predict overall survival after surgery for resectable NSCLC. Not surprisingly, there was a very good correlation, though it wasn’t perfect (patients can die from side effects of the treatment, or from unrelated but competing medical problems).
In the process of reviewing the data from two “meta-analyses” of multiple smaller studies of chemotherapy after surgery, either with or without radiation also administered, a group led by Dr. Michiels from Institute Gustave-Roussy in Villejuif, France reported on the “lead time” that diseease-free survival gives in predicting overall survival. They found that, if recurrences were going to ever happen, about 50% occurred within the first year, at least two-thirds within two years, and about 80% or more within three years.
This is the first of a series of podcasts we’ve done, developed in partnership with LUNGevity Foundation, in which I present the same challenging cases in lung cancer management to a series of experts to learn the range of views offered by them, then the multiple thoughtful comments by all of them discussing the same single featured case for each podcast. The first discussants in each podcast will be Drs. Bob Doebele from University of Colorado and Jyoti Patel from Northwestern University, who are then followed by other terrific colleagues of mine:
Our first case is a discussion of how they would approach a patient who has a small primary tumor that also has a separate microscopic satellite lesion nearby. Here’s the links to the audio and video versions of the podcast (there isn’t a lot of video to see, by the way), along with the transcript:
A very recent issue of the Journal of Thoracic Oncology, the official journal of the International Association for the Study of Lung Cancer, featured a very good review article by the surgical group at NYU about increasing interest in the concept of whether sublobar resection may be comparably effective as a lobectomy for some patients with early stage NSCLC; this article was also accompanied by a thoughtful editorial by expert thoracic surgeon Frank Detterbeck at Yale. (A review of the different types of lung cancer surgery is available through my prior post, and also a great podcast with thoracic surgeon Dr. Eric Vallières).
The excellent review article starts with the background that the general premise that thoracic surgery has been dominated by the results of a pivotal randomized study published in 1995 by the now-defunct Lung Cancer Study Group that showed that sub-lobectomy in early stage NSCLC patients was associated with a higher risk for loco-regional recurrence, a lower survival at 5 years out, and no significant improvement in lung function compared with lobectomy. However, we can be thankful that there have been many advances in management of lung cancer over the past 15-20 years since the trial was actually conducted. First, squamous cell carcinoma was the dominant histologic subtype of NSCLC at that time, whereas now there is more adenocarcinoma and bronchioloalveolar carcinoma than we used to see. Second, it’s now possible to do many lung surgeries with video-assisted thoracoscopic surgery (VATS) that make it possible to do a safer and less rigorous surgery (either lobectomy or sub-lobectomy). Third, with CT scans getting so much better over time, we’re now regularly detecting many more tiny nodules than ever before. The lung cancers detected based on symptoms in 1991 are different from the asymptomatic lung cancers that may well be detected increasingly by CT screening in 2011. Do we really want to remove 1/5 of the lung capacity for an 8 mm nodule? Because we’re using data from much larger and different cancers when we decide to do that.
With the median age of patients now being diagnosed with lung cancer in the US a little over 70, the question of how best to manage elderly patients with lung cancer is a very relevant but also understudied question. One central debate we often have when considering treatment options for elderly patients who present with smaller early stage lung tumors is whether they should undergo a wedge resection (removes just the tumor itself with a rim of non-cancerous lung tissue around it), a segmentectomy (removal of just a segment of the lobe in which the cancer is contained), or a full lobectomy, the more extensive surgery that removes the entire lobe around the cancer, along with a careful dissection and removal of many lymph nodes (more discussion of these options in this podcast by thoracic surgeon Eric Vallières). A lobectomy is more rigorous and a better operation for the cancer, but if patients have competing medical problems, perhaps a less extensive surgical procedure, a “sub-lobectomy” will do the job well enough and reduce the risk of complications.
Historically, there hasn’t been a lot of evidence to speak directly to this question. In our thoracic oncology tumor boards, we often rely on the results of the report by Dr. Mery and colleagues that reviewed the results in a large database and showed that elderly patients who received a sub-lobectomy seemed to do just as well as elderly patients who received a lobectomy. That’s a retrospective review of a large database, so it would certainly be helpful to add to this discussion. Fortunately, some new information is emerging to help shed further light on the matter.
In a paper just published in the Annals of Thoracic Surgery, Okami and colleagues from Osaka, Japan reviewed outcomes for 764 patients who underwent either a lobectomy or sublobectomy for a stage IA NSCLC tumor between 1990 and 2007. They separated their results by age group, either elderly (defined as 75 or older) or younger. This yielded 133 elderly patients, of whom 79 underwent a lobectomy and 54 underwent sublobar resection, and 631 younger patients (539 lobectomies, 92 sub-lobectomies).
What they found was that there was a striking difference in outcomes in the younger patients; with a 5-year survival of 90.9% and 64.9% (p < 0.0001) for lobectomy and sub-lobectomy recipients, respectively. However, in elderly patients, there was no difference: 5-year survival was 74.3% and 67.6% (p = 0.92) for the lobectomy and sublobectomy groups, respectively. These differences are shown in the figures below, in which the top panel shows the survival differences for lobectomy vs. sub-lobectomy for all patients, the middle panel shows patients under 75, and the bottom panel separates out those patients 75 or older:
Both age groups experienced significantly higher rates of loco-regional recurrence after a sub-lobectomy, about 11-12% vs. ~1.5% for each group. Finally, the authors noted that there were no real differences in complications for elderly patients who underwent the more or less extensive surgery.
The staging of lung cancer makes the distinction of whether there are any lymph nodes involved with cancer, and if so, whether they are within the lung that houses the primary cancer or outside of it; if the latter, a distinction is made among mid-chest nodes on the same side as the main tumor (N2), mid-chest nodes on the opposite side from the main tumor (N3), or above the collarbone (N3). This staging is described in more detail in a summary chapter in the lung cancer reference library on initial workup and staging of lung cancer.
But there may also be useful distinctions to be made. I’ve previously described some investigational work suggesting that the number of lymph nodes involved may have prognostic value. Another concept that is commonly accepted is that the risk of recurrence is lower if a patient has a lymph node involved just by direct extension of the cancer into an adjacent lymph node, as opposed to spread to lymph nodes that are some distance away from the primary tumor and therefore presumed to have spread through lymphatic channels. A Japanese study reviewed results in patients with resected early stage NSCLC and N1 nodal disease in order to address this question.
A prior publication by the same group from earlier this year looked at outcomes from just patients with squamous NSCLC who underwent surgery and had N1 disease as their highest stage. Among the 120 patients with N1 nodal disease, the 5-year survival was 67.7% in those with just direct extension, compared with the significantly inferior 5-year survival of 32.4% in those with distant spread, a result that was comparable to that seen in patients with N2 nodal involvement. The current effort looked at a much larger group of 324 consecutive patients with pathologically confirmed N1 nodal involvement, including patients with both squamous and adenocarcinoma histologies. They compared these results to those of 1524 patients with node-negative disease, and 330 others with N2 nodal disease (N3 nodal involvement is generally considered to not be best managed with surgery). The investigators reviewed whether there were differences in the overall NSCLC population and also looking specifically at the histology of the NSCLC tumor, as squamous tumors have a tendency toward more local spread and adenocarcinomas tend toward earlier spread to distant sites, although these are only general tendencies.