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Different Chemo Choices for Concurrent Chemo/Radiation
My last post included studies that demonstrated no additional benefit from giving chemo after concurrent chemo/radiation for locally advanced NSCLC, but it’s important to add a qualifier to that conclusion. The studies that have shown an overall favorable result from two cycles, or about 6-7 weeks, of chemo with radiation have thus far primarily been with cisplatin and not carboplatin. As I’ve mentioned previously, there is some evidence that cisplatin and carboplatin, while related drugs and overall similar in performance, may have some differences, and I wouldn’t want to generalize the results in stage III NSCLC from cisplatin to carboplatin and visa versa.
The reason is that cisplatin is unusual among chemo agents in that it can be given at full dose with radiation concurrently. Carboplatin is generally given with paclitaxel when administered concurrently with radiation, and both drugs are given at much lower doses than would be used if patients were not receiving radiation at the same time. The reason is that carboplatin and paclitaxel are very potent radiation sensitizers, and giving these drugs at full dose would likely lead to very significant toxicity problems in the area of the radiation field. So carboplatin and paclitaxel are routinely given at a low weekly dose, which enhances the radiation quite effectively.
The problem, however, is that we’re fighting cancer on two fronts: local and distant. I’ve mentioned this in passing before, but we often need to consider the risk of recurrence within the region of the cancer and also the risk of distant disease. When cisplatin/etoposide or some other cisplatin-based regimens are given with radiation, it’s possible to give doses that both enhance the radiation effect locally and also provide systemic, “whole body” treatment against micrometastases outside of the radiation field. Since the great majority of patients with stage III NSCLC have recurrence distant from the main cancer, giving effective systemic therapy is an important consideration. And it’s not likely that we’re offering that with low dose weekly carbo/paclitaxel with radiation.
We’re now recognizing the issue of a third compartment of the brain more and more, since 20-35% of patients with stage III NSCLC develop disease recurrence in the brain first or brain only. We don’t have an established role yet for prophylactic cranial irradiation in this setting, but it’s something we’ve been studying because the central nervous system (brain, basically) is a potential sanctuary site for untreated micrometastatic disease. Most of our chemo doesn’t seem to get into the brain very effectively due to the blood-brain barrier.
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All of this is basically to say that my conclusion about two cycles of chemo concurrent with radiation being as good as more treatment for stage III NSCLC can only be interpreted as applying to cisplatin. We do have some information about carboplatin-based chemo, generally in the context of induction chemo (chemo before concurrent chemoradiation), and I’ll cover that next.
Questions and Concerns about Consolidation Taxotere
Although consolidation taxotere after concurrent chemo and radiation therapy (CT/RT) emerged as the preferred treatment approach for about 2/3 of American oncologists over the last few years, this was predicated on an incomplete story. We received information from an additional two studies this year, and now it’s a big mess.
In the wake of the small but impressive SWOG 9504 trial (abstract here) that I described in my last post and that suggested a survival benefit from consolidation taxotere, the next trial that needed to be done was a direct test of taxotere. SWOG wanted to do such a trial, but the government agency, the Cancer Therapy Evaluation Panel (CTEP) that oversees cancer cooperative group trials didn’t let SWOG do that trial, because CTEP felt the question was too passé. Instead, they felt that we should presume consolidation taxotere is the new standard, and then test a sexy new drug like Iressa as a maintenance therapy after concurrent CT/RT and taxotere. This trial took shape as SWOG 0023, with the design shown here:
(Click to enlarge) Continue reading
How Did Consolidation Chemo Become a Leading Approach for Stage III NSCLC?
As I described in my last post, there is a strong consensus that overlapping chemotherapy (CT) and radiation therapy (RT) provides greater efficacy, meaning higher survival rates, than a sequential, non-overlapping approach for stage III, unresectable NSCLC. Beyond that, it’s a bit of a mess, with a wide range of choices and no clear “right” choice.
We know that most of the larger trials with CT/RT that have defined our standards have used cisplatin with older partner drugs like vinblastine or etoposide (also sometimes referred to as VP-16). One key advantage of these drugs is that they can actually be given at full dose with radiation at the same time. This means that the chemo can effectively combat potential micrometastases in the bloodstream, as well as provide radiosensitizing benefits, making the RT more effective in the area in which RT is directed (the “radiation field”). In contrast, other commonly used regimens during RT, most commonly carboplatin and paclitaxel, are given at low doses every week, which we don’t believe are systemically effective doses – in other words, although lower doses may make RT more effective, the attenuated doses aren’t enough to kill micrometastatic tumor cells that may lead to later distant (outside of the RT field, such as bone, liver, adrenals, brain, and other places metastases may settle).
Although the long-term survival rates with CT/RT have improved modestly over the past decade or two, we can all agree that there’s LOTS of room to try to improve. One of those ways might be to add more chemo before or after the 6-7 weeks of concurrent CT/RT, particularly if that gives us a better chance of giving good, systemic doses of chemo able to eradicate more distant cancer cells. I’ll cover the ups and downs of follow-up, or consolidation, chemo now. Continue reading
Why Do We Give Chemo/Radiation Concurrently in Stage III NSCLC?
When I first started OncTalk, my first priority was to get some basic posts on the site that provided a quick and dirty assessment of the best standards we had for different stages of lung cancer. But not only did several of these gloss over a lot of material very quickly, that was really before I could add figures. I’m going to try to go over some issues that are on the site in a more thorough manner; how chemo and radiation concurrently became the preferred approach for stage III NSCLC is a good place to start.
Why give chemo and radiation? We need to beat the cancer in two arenas: local and distant. We know we want to cover the tumor we can see with radiation, which can be quite effective in the area it covers, but it can’t treat any micrometastases, living cancer cells that are outside of the radiation field. Chemo can potentially eradicate disease we can’t see that is elsewhere in the body, poised to develop distant metastases. It can also work as a radiation sensitizer (or radiosensitizer), making radiation more effective in the area that receives it, if it’s given at the same time as radiation. So chemo may improve both local and distant control when added to radiation. Continue reading
Is there a Group That Does Particularly Well with Erbitux in NSCLC?
I wrote in a post several months ago about the ongoing study of the monoclonal entibody against EGFR erbitux (cetuximab) in lung cancer, where it’s role is still up in the air. Unlike the EGFR tyrosine kinase inhibitors (TKIs) iressa and tarceva, which showed no benefit when given concurrently with standard chemo, erbitux has a different mechanism and may still be useful when given along with chemo. As I mentioned in my last post, a phase III trial of carbo/taxane chemo with or without erbitux failed to show any improvement in progression-free survival, but it did actually show a higher response rate in the group that received chemo with erbitux. But perhaps there are particular patients who are likely to gain a lot more with erbitux than others, just as we’ve found that certain groups, such as those with EGFR mutations and never-smokers benefit most consistently from the EGFR TKIs.
I previously described the early results on SWOG Trial 0342 (abstract here), in which over 200 patients with previously untreated advanced NSCLC were randomized to two arms. The sequential treatment arm received 4 cycles of carbo/taxol chemotherapy followed immediately by weekly erbitux until progression of disease, while the concurrent arm received the same 4 cycles of chemo along with concurrent weekly erbitux, then followed by weekly erbitux alone. The schema is shown here:
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The early results (abstract here) suggested that perhaps the concurrent arm did a little better, but neither arm did spectacularly, and it was worth debating whether the results were promising enough to commit to larger future studies. This year, Dr. Roy Herbst from MD Anderson Cancer Center presented more updated results (abstract here). With longer follow-up, the two arms converged together, both looking pretty good, with a median progression-free survival (PFS) of 4 months and overall survival (OS)of 11 months. You can see that the survival curves for the two groups are basically on top of each other:
Trial of Chemo with or Without Erbitux in Advanced NSCLC Negative
It’s a little sad that you can get more cancer information from the business websites than from the medical ones, but if you checked a story on Forbes.com today you learned that Bristol-Myers Squibb (BMS) provided a press release that one of their important Erbitux (cetuximab) trials didn’t meet its primary endpoint of improved progression-free survival for chemo with Erbitux compared with the same chemo alone.
Erbitux is another inhibitor of the epidermal growth factor receptor (EGFR), similar to Iressa and Tarceva, but unlike those oral pills, Erbitux is an IV drug that is actually a monoclonal antibody to the part of the receptor that is on the outside portion of the cancer cell (extracellular). Erbitux definitely has activity in some cancer types: it’s FDA-approved in treating colon cancer and head and neck cancer. But there have been some negative studies with Erbitux as well in other tumor types, including a large trial of chemo with or without Erbitux in pancreatic cancer that showed no benefit to the Erbitux combination (abstract here). It’s also been studied in lung cancer, primarily in NSCLC, with some modestly encouraging results, but definitely not a slam dunk. I’ve described some of this work in a prior post. Continue reading
Biologic and Molecular Correlates of Clinical Benefit in French Trial of Iressa in BAC
The study I was just discussing, the French trial of Iressa at 250 mg daily for advanced BAC (abstract here), provided interesting clinical information, especially when viewed in the context of previous work on EGFR inhibitors in BAC. But in 2007 we’re also interested in the next generation of questions, including trying to identify which patients are more or less likely to benefit from Iressa or other EGFR tyrosine kinase inhibitor therapy. In addition to the clinical portion of the trial, the French investigators evaluated several clinical, pathologic, and molecular variables that were associated with disease control (DCR: response or stable disease) vs. progressive disease (PD) in a separate reported part of the study (abstract here).
From the 88 eligible patients enrolled on the BAC trial, they had tissue submitted from 65, of whom the expert pathologists felt that 50 had BAC or adenoBAC, evenly split between mucinous (M) and non-mucinous(NM) BAC, while the others didn’t have tumor tissue in their submitted specimen or had an adenocarcinoma that the experts didn’t think could be called BAC (this is typical — expert reviews of pathology submitted as “BAC” from various hospitals often show high rates of disagreement, with a less strict definition in the “real world”). Not suprisingly, the patients with tissue submitted, like those on the trial in general, had a higher rate of non-smokers (>40%, and from France, no less!), and more than half of the BAC patients were women (pretty much the only lung cancer setting where we see this). The tumor tissue was tested for EGFR by protein expression (immunohistochemistry, or IHC), gene amplification (by a process called FISH, and another called CISH), and also for EGFR mutations; they also checked for ras mutations, which I described in a prior post as being likely associated with a lower likelihood of benefit on EGFR inhibitors. Finally, they checked for thyroid transcription factor-1 (TTF-1), which is a marker of thyroid and lung tissue that helps us determine whether a cancer is actually from the lung or thyroid vs. another part of the body (they can tell the difference between lung and thyroid from other protein stains in the unusual cases where there’s a question between those sites as the primary tumor site). About 70% of lung adenocarcinomas express TTF-1.
First, the investigators compared the M-BAC to NM-BAC tumors and found differences in several regards. Although there were no gender differences and never-smokers were found in similar proportions between the two types of BAC, NM-BAC was much more likely to be associated with TTF-1 expression, EGFR protein overexpression (by IHC; about 35%) and gene amplification (by FISH and CISH; 10% range)) and EGFR mutations (12% of the population) than M-BAC tumors. They didn’t differ in their frequency of ras mutations (about 1/4 of both groups). So they have some differences that might explain differences in how the different types of BAC tumors respond to EGFR inhibitor therapy.
And when they looked at the characteristics of the patients who achieved disease control vs. those who showed PD, they saw that the patients who had stable disease or better were significantly more likely to be women, never-smokers, have NM-BAC, have a tumor that expresses TTF-1, and also a higher likelihood of having an EGFR mutation. In contrast, those with ras mutations were more likely to be the ones who showed progression. Here’s the summary:
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This isn’t a large enough study to say anything definitive, but it’s a step forward in giving us hints about biological differences between M-BAC and NM-BAC, and it also helps provide some insight about why people with NM-BAC may be more likely to respond better and have longer survival on Iressa and Tarceva trials. In addition, this biological information may be useful outside of BAC. Perhaps the patients with TTF-1 positive tumors are the ones more likely to respond to EGFR inhibitors. We’ve never really looked at that, but that marker is a routine part of testing lung tumors. It’s readily available everywhere, and it doesn’t take days or weeks to obtain, unlike the mutation work. There are several other interesting leads here, so we need to follow up and see what holds up in other studies of EGFR inhibitors.
France Weighs in on EGFR Inhibitor Therapy for BAC; Mucinous vs. Non-Mucinous BAC
I reviewed a couple of presentations on bronchioloalveolar carcinoma (BAC) at ASCO 2007, including one by Cadranal and colleagues in which patients with advanced BAC received single agent Iressa (abstract here). This study enrolled 88 eligible previously untreated patients with advanced BAC or adenocarcinoma with BAC features, about 55% women/45% men (typical for BAC trials to have slightly more women than men, unlike other types of lung cancer) to receive Iressa at 250 mg daily. They did a repeat CT scan three months after starting Iressa and looked at the disease control rate (DCR), the combination of responses and stable disease, in patients at that point. The response rate of 13% and disease control rate of 29% were just a little lower than other trials of EGFR inhibitors in BAC (one of Iressa at 500 mg daily in the US that I led (abstract here), and another of Tarceva at 150 mg daily that was led by Drs. Vince Miller and Mark Kris at Memorial Sloan Kettering (abstract here)). While the French group didn’t report a median survival, they did report a one-year survival of 52% that was right in line with my earlier US-based study, so it didn’t appear that a lower dose of Iressa was associated with a worse outcome. Here are the available efficacy results for the three similar trials, side by side:
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As we’ve seen as a recurring theme, in all of these trials women did somewhat better than men, never-smokers did better than former or current smokers, and the people who developed a rash also did better than the ones who didn’t develop skin toxicity.
One way in which the French study moved things along in the world of BAC was by noting differences in outcome between the half of patients with mucinous BAC vs. those with non-mucinous BAC, among the 65 who had tissue available for study. They found that the folks who had non-mucinous BAC did considerably better on the Iressa trial than those with mucinous BAC:
That would perhaps just be an interesting curiosity, except that we saw the same significant difference, with significantly better results with Iressa in the patients on our SWOG trial who had non-mucinous instead of mucinous BAC (reported in a separate abstract here):
We haven’t seen any analysis like this yet from the Memorial Sloan Kettering trial with tarceva, but with the two trials that have looked at this issue showing the same exact finding, it does seem that Iressa, at least (and I’d suspect it’s the same with Tarceva) is particularly helpful with the non-mucinous form of BAC. Interestingly, the small study of taxol (infused slowly over four days; abstract here) actually showed that the responses were in patients with mucinous BAC, and that there were no responders with non-mucinous BAC, although the actual number of patients who had tumor tissue available for analysis was very small. This remains an open question, but it’s possible that mucinous BAC may be more responsive to chemo and that non-mucinous BAC is more responsive to the EGFR inhibitors like iressa and tarceva.
We’ll be studying this a lot more in the future, but at this point we might actually want to begin to subdivide BAC into different groups to see if we can refine best treatment plans by whether patients have the mucinous or non-mucinous subtype. They appear to actually be somewhat different diseases.
Risk of Complications when Avastin Combined with Chest Radiation
After Avastin was found to produce a survival benefit when combined with chemo in advanced NSCLC, it became increasingly appealing to try to see if adding Avastin in earlier stages of lung cancer, both SCLC and NSCLC, where it might increase the cure rate. I’ve described how it’s being studied in a trial with post-operative chemo (prior post here), but another place where it’s being studied in the potentially curative setting is locally advanced NSCLC and LD-SCLC. However, a trial of Avastin combined with chemo and radiation for LD-SCLC was actually stopped early due to the appearance of an unusual and serious complication that may be a real problem, leading to a great deal of caution in this line of research.
As described here, a trial in LD-SCLC that combined carboplatin, irinotecan, and avastin with radiation stopped after 29 patients were enrolled, because two confirmed cases of tracheo-esophageal (T-E) fistula (a connection between the trachea (windpipe) and esophagus) were confirmed, of whom one died, and a third patient also died with a suspected but not confirmed T-E fistula. So if there were about 10% of patients with a life-threatening or fatal side effect, that’s a red flag, and this led the manufacturers and the FDA to issue a warning about it. The official packaging information will also reflect information on this issue in the future. At least six other cases of T-E fistulas associated with chemo or radiation, have been reported to the company, and others may come as this information becauses available. In the lung cancer conference I co-chair here, my colleagues and I presented a patient who was treated elsewhere and had received prior chemoradiation, then chemo and avastin, and developed an enormous fistula that was sent to our center to manage. Our surgeons noted that this was the largest T-E fistula they had ever seen in their careers, so at our meeting we publicized the case and raised the question to our participants whether thay had seen similar cases (they hadn’t). So the closure of that trial didn’t come out of left field for me. We suspected that avastin could be related to development of fistulas in patients who received radiation, but one case doesn’t make a trend. We’re providing details of our case to the company. Continue reading
Integrating Avastin into Treatment of SCLC
In a talk at ASCO 2007, I was asked to present some commentary on a couple of phase II, single arm trials of patients with ED-SCLC that were reported by two different cancer cooperative groups in the US, each adding the anti-angiogenic agent Avastin (bevacizumab) to standard chemotherapy options in this setting. One trial, CALGB 30306 by Ready and colleagues (abstract here), added Avastin (15 mg/kg) every three weeks to a chemo regimen of weekly cisplatin and irinotecan (camptosar, CPT-11), each given two weeks out of a three week cycle, for up to 6 cycles, with no “maintenance” avastin alone after stopping the chemo. The second, ECOG 3501 by Sandler (the same Alan Sandler who led the advanced NSCLC trial ECOG 4599 that led to the FDA approval of Avastin in lung cancer) and colleagues (abstract here), combined Avastin at the same dose every three weeks with cisplatin and etoposide, stopping the chemo after four cycles, but continuing with maintenance avastin alone until patinets showed progression. Interestingly, these exact regimens, including the same schedules and doses of the chemo drugs, were compared to each other in a study by Nasser Hanna and colleagues that was published in 2006 (abstract here), so the performance of these chemo regimens in this phase III trial (that showed no significant differences in activity) can serve as a benchmark of what we should expect the chemo to do without avastin. Here’s a summary of the two trials side by side, along with the general profile of the patients in each trial:
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As is typical for other lung cancer trials, patients with a history of coughing up blood (hemoptysis) or with evidence of brain metastases were not eligible for these studies. Each enrolled a little more than 60 patients. Continue reading
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