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Pre-Operative Chemotherapy as an Alternative to Post-Operative Chemo: Evidence of Stage-Dependent Survival Benefit
In contrast with post-operative chemotherapy, which has become a standard treatment approach to reduce the probability of recurrence of resected stage II and IIIA NSCLC (still pretty controversial for stage IB), pre-operative chemotherapy (also known as neoadjuvant, or induction chemotherapy) is less well studied and isn’t a typical approach. However, a recent study called ChEST, the Chemotherapy in Early Stages Trial, was presented at ASCO (abstract here) and showed a borderline positive survival benefit with neoadjuvant chemotherapy, despite the fact that the trial was stopped very early. As a trial of chemo followed by surgery vs. initial chemo followed by surgery, and post-operative chemotherapy had been shown in several trials to improve survival in this population, the Data Safety Monitoring Board felt it was unethical to continue a trial in which half the patients receive no opportunity for chemo either before or after surgery.
As shown below, the trial enrolled 270 of an initially planned 700 patients before closing early, and these patients were randomized to receive upfront surgery or three cycles of cisplatin/gemcitabine followed by surgery:
Importantly, more than half of the patients enrolled had stage IB or IIA disease. As you’d expect, this group has a better prognosis than patients who have stage IIB or IIIA resected NSCLC, and therefore potentially less to gain from chemo.
Long-Term Risk with Adjuvant Chemo
Over the past few years, the role of post-operative, also known as adjuvant, chemo has become increasingly accepted as a standard of care. Several trials have shown an improvement in survival at about 5 years that is in the 5-15% range for recipients of chemo. However, the evidence indicates that the people at higher risk receive more benefit, as you’d expect: the risks of chemo are the same no matter what stage cancer someone has, but if the chemo reduces the recurrence rate by a similar fraction for everyone, the person with a 60% risk of recurrent cancer is going to benefit far more than the person with a 25% risk of recurrence. And many of our trials have failed to show a benefit for patients with resected stage I NSCLC, at least for those with cancers smaller than about 4 cm.
I think many oncologists and patients think of adjuvant chemotherapy as either helping significantly or not helping significantly. But there is some limited evidence that demonstrates that some people really may be harmed by chemo, either during the time of chemo, or perhaps more distantly in the future. For instance, I described early work (prior post here) on a marker called ERCC-1 that is correlated with resistance to cisplatin (low expression is associated with sensitivity to cisplatin-based chemo and better outcomes after adjuvant chemo, while high expression is associated with resistance to cisplatin-based chemo and worse outcomes). In fact, that large subset analysis showed that patients who showed high ERCC-1 expression — a pattern of resistance — actually did modestly worse than patients who were observed and received no chemo. So it may not just be that we need to understand better who is going to benefit more and who will benefit less, but rather that we need to predict better because the ones we aren’t helping we may actually be harming. We can overtreat as well as undertreat.
In fact, one of the more interesting presentations at ASCO on the subject of lung cancer was a report of the eight year follow-up of patients on the International Adjuvant Lung Trial, or IALT. This was presented initially at the plenary session at ASCO 5 years ago (abstract here), where we saw the first convincing evidence of a survival benefit from post-operative chemo, and then it was published in the New England Journal of Medicine (abstract here) as a new standard of care. It enrolled 1867 patients with resected stage I to stage IIIA NSCLC to receive post-operative observation alone or any of 4 cisplatin-based chemotherapy regimens:
Erbitux with Radiation in More Marginal Patients with Locally Advanced NSCLC
One of the core ideas in the management of stage III, or locally advanced, NSCLC is that unresectable disease that is being treated with curative intent is most effectively treated with a combination of concurrent systemic (“whole body”) therapy and chest radiation to all of the visible cancer. The systemic therapy, which has been conventional chemotherapy, is given to both make the radiation work better and to treat potential micrometastatic disease, cancer cells in the bloodstream that can’t be reached by radiation but could potentially be killed off by a treatment that goes throughout the bloodstream.
The challenge, though, is that concurrent chemo and radiation is hard on people, with a rate of treatment-related deaths of about 5-7% of people even on clinical trials (which often select for a fitter population than are seen in the “real world” of many ineligible patients). So we reach a point where the aggressiveness of the treatment can be associated with problems that are as threatening or worse than the underlying disease. And this is a particular problem for older and/or frailer patients, which happens to cover a significant proportion of people with lung cancer.
Part of the promise of targeted therapies all along has been that they could potentially substitute for standard chemotherapy as a systemic therapy that is perhaps as effective as chemo but with fewer side effects. Most of our work with these agents has been to just add them to our current standards, but it still makes sense to consider using them as a substitute in patients for whom conventional chemo is really at the upper limits of what is tolerable. And it’s clear that doing chemo concurrent with radiation is overall more effective than doing them sequentially, but perhaps we could get the tolerability of a sequential approach with the efficacy of concurrent therapy by doing a program of targeted therapy (and no chemo) concurrent with chest radiation.
Integrating Alimta and Cetuximab in Locally Advanced NSCLC
As a follow-up to my last post on the appeal of developing new regimens for combining with radiation in treatment of locally advanced unresectable NSCLC, I wanted to highlight work being done by the Cancer and Leukemia Group B (CALBG), one of the major cancer cooperative research groups in the US. As I mentioned previously, we’ve had difficulty developing widely accepted alternatives for the few chemo regimens commonly used in combination with concurrent radiation — primarily cisplatin/etoposide or weekly carbo/taxol. Some experts feel that weekly carbo/taxol has a shortcoming in that it is given at a more frequent but lower dose than the “full dose” every three week regimen, and the lower dose may have very little activity against micrometastatic cancer cells traveling throughout the bloodstream. For that reason, it may be preferable to give full, “systemic dose” chemo at least at some point during treatment for locally advanced NSCLC, and giving it during radiation could allow you to treat a person for both local cancer in the chest(disease you can see and treat directly, with radiation, while chemo bolsters the radiation — called chemosensitization) and distant disease outside of the radiation field. But there are relatively few chemo regimens that can be given safely at full “systemic” doses with radiation concurrently. The CALGB lung cancer committee has been working on a new regimen that incorporates a regimen of carboplatin and alimta one day every three weeks at full dose, with radiation, an approach that could potnetially be enthusiastically adopted in the lung cancer community as a newer and more convenient alternative if it looks as good or better than our older standards.
Now that there is evidence from early safety/feasibility studies that chest radiation can be given along with full dose alimta every three weeks along with carboplatin (abstract here) or cisplatin (abstracts here and here), CALGB developed a trial to test the activity and safety of carbo/alimta/RT followed by alimta “consolidation”, or the same strategy with erbitux added throughout, both during the radiation and afterward, with the alimta consolidation (abstract here). The trial design is as shown here:
Introducing Erbitux and Other Agents into Treatment of Locally Advanced NSCLC: RTOG Experience
While there have been new agents introduced and rapidly changing standards in advanced NSCLC, another 40% of patients with NSCLC have locally advanced (stage III) NSCLC, many of whom with disease that is not resectable but is potentially curable with agressive chemo and radiation. Last year’s ASCO meeting included results that strongly suggested that consolidation taxotere after 6-7 weeks of concurrent chemo and radiation may not add a benefit, and in an important trial by the Hoosier Oncology Group (affectionately known as the HOG), the best treatment was with just two cycles of cisplatin/etoposide chemotherapy along with radiation (as detailed in a prior post).
Many oncologists, myself included, have been reluctant to accept that just two cycles of chemo and seven weeks radiation are really enough to treat stage IIIB disease, which is clearly more of a threat than stage II NSCLC, for instance, and for which we standardly give four cycles of platinum-based chemo. Most US-based oncologists give either two cycles of cisplatin/etoposide with concurrent chest radiation, or weekly low-dose carboplatin/taxol for about 7 weeks while a patient is getting radiation, and it’s a bit unsettling to think that either there aren’t potential improvements to be made by adding new agents, either to replace some of our older standards or to add along with the chemo/radiation concurrently or as a different consolidation therapy. Cisplatin/etoposide/RT has been used now for both limited SCLC and locally advanced NSCLC for 20 years, so we’re all impatient to see new agents take their place and define some new standards.
Consolidation Radiation to Residual Chest Disease After Chemo for Extensive SCLC?
Here’s a situation in which I learned something from the questions raised by people here online. A handful of people with extensive disease small cell lung cancer (ED-SCLC) in the last year or two have mentioned receiving radiation for areas of residual apparent disease after receiving initial chemotherapy. I had noted that I had never done this and didn’t really see a clear rationale for pursuing a local treatment like radiation for a disease that has already declared itself as spreading throughout the body. But while there is no good evidence to say that radiation should be included after chemo, it is actually an open question, and there are some recommendations that say it’s something to consider under certain conditions.
The question of whether radiation should be added routinely to chemo for ED-SCLC was the subject of several very old studies from 20-30 years ago, and they didn’t show any clear benefit. However, radiation has changed a lot in that time, and in truth, several studies that compared chemo alone to chemo/RT were so small that they couldn’t say anything meaningful. In fact, there was a single study published based on the combined efforts of groups in Germany and Japan (abstract here) that randomized patients who experienced a complete response (no evidence of disease) outside of the chest and either a complete or partial response in the chest to either additional chemo alone after platinum/etoposide chemo, or chemo and aggressive chest radiation. The results looked more facorable for the patients who received radiation in addition to chemo, although only 109 patients were included in the relevant analysis. Again, this was only in the patients who had a complete response and no evidence of cancer outside of the chest after initial chemo. As you might expect, radiation was associated with sometimes significant esophagitis (painful inflammation of the esophagus).
Unfortunately, I don’t believe there’s been any further assessment of this question presented or published in the last decade. Based on the rather scant evidence but some hint of a possible benefit, the American College of Chest Physicians has included in their evidence-based guidelines about managing SCLC (abstract here) that, while not a clear recommendation, it is reasonable to offer chest radiation to patients with ED-SCLC who have a complete response outside of the chest and a complete or partial response within the chest, acknowledging that this is a concept based on pretty weak evidence.
Still, I wanted to highlight this because it represents a situation in which I learned something new that will probably change my treatment approach, based on what people here described. I want to ensure that I’m open to new information and can not be wedded to just doing things the way I’ve previously approached them, if there is more information. In this case, the little information available goes back a long ways, but it suggests that it could be appropriate to be open-minded to the idea that “consolidation radiation” to the chest might be helpful even for extensive 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.
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:
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