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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
Randomized Phase II Trial with Erbitux Looks Favorable
The antibody to the epidermal growth factor receptor erbitux (cetuximab) (introductory post here) has been used as an effective treatment for colon and also head and neck cancer for several years, but its role in lung cancer has yet to be defined. Early work in lung cancer was not especially impressive (prior post here), but in September, 2007, a press release reported that the FLEX trial, a European randomized study for first line advanced NSCLC that gave cisplatin/navelbine with or without erbitux, was positive with a statistical survival benefit (prior post here). Several months later, we’ve got no more information than that press release, but we do know that the trial was designed to require a survival benefit of at least 20-25% (I’ve never gotten a firm answer on this) from chemo/erbitux compared with chemo alone to be positive, so presumably it achieved a pretty impressive result that should be clinically relevant, offering a survival benefit in the same range as adding avastin to chemo for first line advanced NSCLC.
In the setting of mixed results and unreported positive trials, additional signals that can validate positive results are particularly helpful. A randomized phase II trial by Dr. Charles Butts and colleagues that enrolled first-line advanced NSCLC patients to receive either platinum-based chemo alone or with erbitux was presented at ASCO this year (abstract here), and the results were provocative, but the trial was small, with just 131 patients, and in the absence of a larger trial demonstrating the benefit of erbitux, it didn’t blow me away.
The full manuscript was just published in the Journal of Clinical Oncology (abstract here), and while it’s still a small study that won’t change the world, it now corroborates the positive FLEX trial and therefore has a new significance, to my eye. The schema was that previously untreated patients would be randomized to receive platinum (cisplatin or carboplatin) with gemcitabine on three week cycles, either alone or with weekly erbitux:
(Click on image to enlarge) Continue reading
Oral Topotecan FDA Approved in US for Second Line SCLC
This bit of news slipped under the radar for the past six weeks, but oral topotecan was approved by the FDA for the treatment of SCLC that has recurred at least 45 days after the last chemotherapy had been given. I’m a little embarrassed to say that I hadn’t noted this, but it really got very little airplay. Part of it is that topotecan was already available and approved for recurrent SCLC in its IV form. But as you can review in my summary post about it, the prior FDA approved form of topotecan, as a regimen given IV for five days in a row each 3 week cycle, makes for a rather inconvenient approach for many patients. Giving IV topotecan on a weekly schedule is a feasible alternative, but it hasn’t been as well studied as a five consecutive day schedule. While IV and oral topotecan have been shown to have the same activity overall, it was actually the oral topotecan formulation that was recently shown to have a significant survival benefit compared with supportive care alone for recurrent SCLC. I described that in the post referenced above, in which I also said that while oral topotecan wasn’t approved yet, it likely would be soon. It should be routinely available in 2008.
I’ll also mention that oral topotecan happens to have been studied in second-line NSCLC as well. In a trial that randomized over 800 patients with previously treated advanced NSCLC to either IV taxotere on day 1 (the first FDA-approved second line NSCLC treatment) or oral topotecan for five days every 21 days (abstract here), Ramlau and colleagues reported that oral topotecan produced a similar but borderline significantly inferior overall survival rate. This is illustrated in the figure below, where the curves are close, but taxotere is always on top by a small margin:
(Click on image to enlarge)
While oral topotecan appeared perhaps just a shade inferior in activity, it was actually rated overall a little worse in quality of life in this study as well. Measured side effects were pretty comparable overall. Continue reading
Duration of First-Line Chemo in Advanced NSCLC: 4 vs. 6 cycles
Although I’ve previously written about the question about optimal duration of therapy for first-line chemotherapy in advanced NSCLC (post here), these conclusions have been based on a limited number of trials. One study randomized patients to three or six cycles of rather old chemo and found no significant differences (abstract here). Another more recent study randomized patients to four cycles of carbo/taxol compared with treatment until progression or prohibitive toxicity, with some patients going for more than 12 cycles, also demonstrating no significant differences in survival (abstract here). Based on the rather modest data, the current guidelines of the American Society for Clinical Oncology (ASCO) are to treat for no more than four cycles in non-responders, and no more than six cycles in patients who demonstrate a response to first-line treatment.
Most US-based oncologists follow a practice of treating up to either four or six cycles, although a reasonable minoriity in the US, and a higher proportion in other parts of the world, still treat beyond six cycles and up to the time of progression. Our current clinical trials, developed to include current best treatment practices, incorporate either four or six cycles of chemotherapy, with no consensus. The ECOG 4599 trial that established the role of avastin with carbo/taxol gave six cycles of chemo and avastin together, followed by maintenance avastin (abstract here). On the other hand, multiple trials that have focused on the maintenance portion or timing of second-line therapy have stopped at four cycles (see prior posts here and here). What’s really the best approach?
A trial by Park and colleagues from Korea that was just reported in the Journal of Clinical Oncology tried to address this question (abstract here). As shown in the schema below, 452 patients with previously untreated advanced NSCLC were treated first with two cycles of cisplatin-based chemo, and then responses were measured. One third who showed progression or toxicity problems came off the trial, leaving 314 who experienced stable disease or a response to be randomized to either four more cycles (total of 6) or two more cycles (total of 4) cycles of the same chemotherapy:
(Click on image to enlarge)
Patients were then followed, received a CT every three months after chemo ended, and in most cases received subsequent chemo (off protocol) at that point.
The results demonstrated that the patients who received a total of six cycles had a significantly longer progression-free survival, but both groups had the same overall survival, as shown here:
Differences in side effects weren’t very different between the two arms, with a little more toxicity in the patients who received more chemo, as you’d expect. Quality of life was also measured, and while there were no overall clear differences, a few parameters favored the shorter treatment arm, and none favored the longer treatment arm.
The results are noteworthy for a number of reasons. The authors make the point that the survival is quite favorable, and if the numbers you see look especially good, that is largely because the numbers reflect survival of a group of patients who remained after the third who had progressed or otherwise done poorly came off the study — the only ones randomized were those with stable disease or better after two initial chemo cycles. Second, more than half of the patients on the trial received iressa, and we know that Asian patients are more likely to do particularly well with EGFR inhibitors. At the same time, however, some trials that compare results in Japanese vs. North American trials that used the exact same chemo in the same setting produced more favorable results in the Japanese population. It is possible that patients in Japan do better because something about the supportive care is better, they have more responsive disease, or some combination of factors.
I don’t get a clear answer to the question of whether four cycles or six cycles is a better choice, and frankly I don’t think it matters much. I think that if patients tolerate chemo well and are still demonstrating stable disease, it’s perfectly great to continue to six cycles, but four is going to get people to pretty much the same place. I think the main reason for this is that there’s a dilution of any differences with second line and often third line treatments. An advantage of stopping after four cycles is that it may deliver more patients to later therapies with a good performance status and “bone marrow reserve” — the capacity to have the bone marrow make more blood cells quickly after subsequent chemo. Overall, I wouldn’t have any hesitation about participating in a trial that includes four cycles, nor would going to six cycles be a problem, as long as a patient continues to feel OK on chemo. With several later treatment options available now, and a real possibility (and I’d even say probability) of more new treatments emerging as 2nd, 3rd, or even 4th line options for advanced NSCLC, subtle differences in what happens in first line treatment are increasingly likely to get washed out over time.
FDA Reports Patient Deaths with Radiofrequency Ablation to Lung Tumors
This week, the US FDA made a public announcement to alert the public that it had received reports of several patient deaths from the technique of radiofrequency ablation (RFA) to lung tumors. This is an investigational technique that I described in a prior post, after several members asked about RFA. I made the point that while it was an option to consider, it was still early in development and was not an option that I thought would be a leading option except in very unusual circumstances. You heard it here first…
There have been some individuals and centers that have been liberal in their marketing of this technique, including for lung tumors. The FDA warning highlights the danger of marketing hype getting ahead of the evidence supporting the safety and clinical benefit of a new technique or drug, which really need to be subjected to thorough clinical testing. These trials are well regulated and closely monitored, and their results will move the field forward. Accordingly, the FDA warning mentions that RFA should preferably be conducted on lung tumors in the setting of a clinical trial.
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.
Surgery for BAC: Special Considerations
While there is a lot of variability in the clinical behavior of bronchioloalveolar carcinoma (BAC), there are some commonly observed findings that are now leading lung cancer experts to consider it as a distinct clinical entity worthy of special consideration for management. Among the important areas for potentially special clinical management is in surgical management of early stage disease. As noted in the last post, the most well differentiated BAC lesions have a very low likelihood of demonstrating nodal spread and have a remarkably high survival at 5 years, approaching 100%. However, they can be multifocal through the lungs and are sometimes managed by multiple surgical resections over many years. With that potential to have small, slow-growing lesions emerge over many years and even over decades, but with a very finite amount of lung tissue to work with, BAC lesions have been a leading consideration for smaller, sublobar resections as an alternative to a full lobectomy (see summary of options in post here)that has generally been the default cancer surgery for lung cancer.
Several of the leading thoracic surgeons in the world, particularly those with an interest in BAC and smaller surgeries, converged in NYC in November of 2004 as part of the first “consensus conference” on BAC (I participated on a committee that focused on systemic (whole body)therapy for advanced BAC) to discuss the state of the art and most relevant management questions, from which they produced a report (abstract here). Largely from a collection of Japanese retrospective studies of early stage BAC, a clear picture has emerged. First, lesions that appear on CT as hazy ground-glass opacities (GGOs) (descriptions and examples in prior post) appear to represent noninvasive BAC, while the solid component on CT scans is highly likely to represent invasive adenocarcinoma. Second, smaller lesions (2 cm and smaller) that are predominantly GGO on CT, BAC under the microscope have a remarkably good survival and an exceptionally low likelihood of node involvement.
On the basis of this work, a couple of trials are now being conducted to ask whether small lung cancers can be treated as well with sublobar resections as a full lobectomy. One of these is being conducted in Japan, looking specifically at adenocarcinomas less than 2 cm. A US-based trial, CALGB 140503, is now active and randomizing 1300 patients with peripheral lung cancers up to 2.0 cm to receive either a lobectomy or sublobal resection. The CALGB trial is being conducted with the participation of the other cancer cooperative groups throughout the US, meaning that we’ll be asking this question for a few years to come. In the meantime, lobectomy remains the standard approach for resectable lung cancer, but if there are a subset of people who may be the best candidates for smaller surgeries, who may have cancers least likely to need extensive resection and perhaps most likely to benefit from the sparing of lung tissue that would be valuable to continue to have later, especially if additional lesions need surgery in the future, as may well occur with BAC.
Noguchi Classification of Bronchioloalveolar Carcinoma (BAC)
I had previously written about a spectrum from pure bronchioloalveolar carcinoma (BAC) to invasive adenocarcinoma in one of my first posts here, but the real credit for this concept goes back to Dr. Masayuki Noguchi from the National Cancer Center Hospital in Tokyo, Japan, who characterized a classification system for peripheral lung adenocarcinomas back in 1995 (abstract here). This paper led to the “Noguchi” system of grading the more typical adenocarcinomas from A to D, with some important implications. While other proposed classification systems have been developed, and none is uniformly accepted and used, the Noguchi classification system comes up more than others in describing the continuum I alluded to previously that progresses from pure BAC to invasive adenocarcinoma.
Obviously, this was a Japanese study, which has important implications, because the Japanese world of lung cancer i(LC) s different from that in the US or Europe. In Europe, LC is still very disproportionately male, related to tobacco, and about 50% squamous cancers, while Japan is the other extreme, with some studies showing a closer balance of women and men, 30-50% of patients as never-smokers, and remarkably few cases of squamous cancer, with LC being comprised of generally adenocarcinoma and its well-differentiated subset. A North American population generally shows results between these two extremes.
The Noguchi study involved a detailed analysis of 236 patients with peripheral adenocarcinoma lung tumors (near the outer edges of the lung), all 2 cm or less in diameter. The specifics of the grading system and the definitions of the classes are complex and worth knowing only if you’re a pathologist carefully reviewing tissue and describing lung tumors. The important the highlights are that groups A to D are far more common than rare adenocarcinoma subtypes known as tubular and papillary adenocarcinoma, and also that there is a gradation from A to D of most differentiated to least differentiated. Men comprise the vast majority of group D, while the sexes are much more evenly split in the groups that are well differentiated and would be considered BAC or a variant. The likelihood of finding nodal involvement was also related to the Noguchi group; no patients in groups A or B had any lymph node spread of their cancer, compared with 28% in group C and 48% in group D. In addition, pleural involvement and vascular invasion were significantly more common in groups C & D than in groups A & B. Growth and cell division were also factors, with the rate of cell division far higher for the less differentiated cancers. The number of mitoses (my-TOW-sees), or cells in the process of dividing on a detailed look at the slide, was more than 5 per “high-powered field” in only 6% of groups A & B, compared with 26% for group C, and 53% for group D. But the most important factor, correlating with the rates of cancer cell division, was survival, which was 100% after 5 years for groups A & B, but lower as you move stepwise from type C to type D:
(Click on image to enlarge)
This type of trend has also been seen outside of just BAC and adenocarcinoma; I’ve written that tumor grade is well correlated with survival (see prior post), and specifically that people with well-differentiated LC do better overall than those people with poorly differentiated tumors.
One other important point is that this study demonstrated that patients with small, peripheral, and very well differentiated lung adenocarcinomas had a survival of 100%, while none demonstrated evidence of nodal spread. This raised the question of whether it’s necessary to do as extensive a surgery in the setting of a well-differentiated lung adenocarcinoma as you would routinely do for other cancers. If the prognosis is outstanding, perhaps we can do smaller surgeries and still achieve such excellent results. I’ll cover the question of optimal surgery for small and well-differentiated lung adenoarcinomas later. This raises the unusual but welcome question in the field of LC, “what is the least we can do to still nearly assure ourselves of excellent results?” Could less be more?
More Challenges with EGFR Rashes
Rashes from EGFR inhibitors: we like to see them, because we know that many trials have shown that skin toxicity on drugs like tarceva is associated with better survival (see prior post), but the fact is that sometimes a rash is more than an inconvenience and can really make people miserable, or at least pretty unhappy, as described in the comments and questions from a discussion forum thread today. I’ve described some general management principles for rash in another prior post, but in truth, oncologists aren’t well trained in rash management, and we’ve generally had to learn as we go along, because EGFR inhibitors have introduced this as a new problem in oncology. Tarceva is a well established treatment at this point for lung cancer, and while the monoclonal antibody Erbitux has been used primarily in colon cancer and head and neck cancer thus far, a major lung cancer trial with erbitux was also recently reported as positive (post here), so there’s a strong possibility that erbitux, which is also associated with very significant rashes (and better survival correlated with that), will also be used increasingly for lung cancer.
But there may be more to managing these rashes than the basics I described in prior posts. One of the leading experts is Dr. Mario Lacouture, a dermatologist from Northwestern Univ., who has published some proposed guidelines that are an alternative to some of the other approaches I had previously described (paper here, with a rather complex algorithm figure included). This work focuses on early and aggressive use of minocycline (synthetic tetracycline) and elidel cream, a treatment developed and approved for eczema. In truth, I haven’t used this yet, but I’ve heard from some people who have that Elidel and this general approach can be very helpful.
Dr. Lacouture is included in a panel on a CME program that is available on the web, “The Conundrum of Rash in Management of EGFR Inhibitors“, which includes a detailed and somewhat complex medical presentation (the target audience is doctors) but that also includes several accessible take-home points. It’s available through that website as a 70+ minute streaming video program, or a podcast or MP3 audio file, or you just download the transcript. One thing that the program highlights, in addition to the point that “oncologists are bad dermatologists” (sad but true), is that there is also the ongoing question of whether and when to temporarily hold the EGFR inhibitor therapy and then drop to a lower level. In general, while we’d try to manage people on the highest dose feasible, these are treatments that have the potentially to be chronically helpful. Because of that, I do see it as a question of what is the lowest dose needed to get the desired effect. if someone is having trouble managing on 150 mg and has been stable for many months, I think it’s appropriate to test whether they might feel FAR better on 100 mg and have just as stable disease, or an ongoing response. While we’ve seen that patients who develop a severe rash can do particularly well, there’s no evidence I’m aware of that people who lowered the dose subsequently (and felt better) did any worse than those who continued to suffer at the highest dose they could tolerate with difficulty.
Overall, it’s good to see that we’re starting to see more dedicated study of these EGFR-based rashes, and to get more actual results from these experiences. I think we’ll need to continue to balance between aggressively managing side effects and to learn whether we need to dose to the borders of tolerability or whether reducing dose to a more comfortable chronic solution is appropriate.
Genetic Differences in Never-Smoker Lung Cancer
As I’ve mentioned in some prior posts, there is increasing recognition that lung cancer in never-smokers may be a different disease. Some of this has been defined by working backward from treatment results, where we’ve seen that never-smokers are consistently among the greatest beneficiaries of EGFR inhibitor therapies like Iressa or Tarceva. But there are some general principles and recurring themes with regard to the genetics of lung cancer in never-smokers.
In most cases, lung cancer develops from an accumulation of mutations in a cell over many years, even decades. A multitude of problems in the cell control mechanisms need to go awry before a cancer can grow rapidly and independently of inhibitory signals, while still having a blood supply and getting waste removed. The checks and balances within the cell are so complex that it often takes more than 10 or even 20 mutations in the same cell before it reaches the “critical mass” to become a cancer cell. For lung cancer, most of these mutations are induced by tobacco smoke. Because of these trends, lung cancer is a disease more common with advancing age, with a median age now for initial presentation of about 70 years.
In contrast, never-smokers appear to develop cancer not from an accumulation of multiple mutations that aggregate over the course of many years to eventually become a full-fledged cancer, but rather from a random few mutations that very efficiently derail the cellular control mechanisms. Therefore, tumors from never-smokers tend to have a much smaller array of problems and be “genetically simpler” (abstracts here and here).
Although it was a small study, one trial provides a good illustration by comparing “gene signatures”, the genetic profiles looking at a collection of potentially relevant genes, from tumor and non-tumor lung in six smokers with lung adenocarcinoma compared with the tumor and non-tumor lung tissue from six never-smokers (abstract here). The authors found that four times as many genes were different between the lung cancer tumor and normal tissue of never-smokers compared with smokers.
(Click on image to enlarge)
This suggests that lung cancer develops out of collection of shared defects throughout the lungs in smokers (a field defect), but in never-smokers, the tumor arose due to a random event pretty much out of the blue. Another corollary of this concept is that the genetic profiles of the tumor tissue in smokers is very similar to the non-tumor lung tissue in the same person, and very different from tumor tissue in never-smokers, which is very different from non-tumor tissue in the same never-smoker. While we’re talking about tissue results from just a dozen patients, these results are very intriguing and have led to larger subsequent studes that are trying to characterize genetic differences between smokers and never-smokers who develop lung cancer.
Of course, one key question is whether there are therapeutic implications here. I believe that there are, as I’ve described in the subject archives on never-smoker lung cancer, and/or the core concepts section just to distill down to the basics. As I mentioned above, EGFR appears to be a central part of this story, but to me the general principle is that if never-smoker lung cancer is often much more genetically simple, if we happen to hit it right we can make a very striking and prolonged input. We haven’t even really begun to give a good luck at whether never-smokers may respond unusually well to standard chemo or avastin or some other novel therapy. All we know is that they are the most common MAJOR beneficiaries of EGFR inhibitors like tarceva. But the next big question is whether there are other drugs out there that can have anything close to the impact of tarceva in never-smokers. The trials dedicated to never-smokers are just starting to get off the ground.
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