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Chemotherapy for Brain Metastases: More Helpful than It’s Given Credit For
There’s a general concept out there that chemo is ineffective in treating brain metastases, and in fact, I’ve mentioned it in some comments here in the past. The reasoning behind this is that we know there’s a blood-brain barrier, and we’ve presumed that chemo is blocked from crossing it. But when CT or MRI scans are done with IV contrast, it often collects in brain metastases, and there’s also often edema around brain metastases: these observations suggest that the blood vessels around brain mets may be disrupted. One study, for instance, showed that in patients who received chemo before surgery, cisplatin concentrations in brain metastases were the same as the levels in tumors outside of the brain (abstract here).
But the more important issue is that in the studies that have actually looked at responses of brain metastases in patients who received chemotherapy and not radiation. In a series of trials that actually directly compared responses of chemo inside and outside of the brain, the response rates in the brain were very similar to the response rates elsewhere in the body. For instance, an Italian study by Crino and colleages (abstract here) included patients with brain metastases (15-17% in the two chemo arms being compared) and found response rates of 39-41% of the brain metastases, actually higher than the response rate outside of the brain. Another interesting trial by Robinet and colleagues from France directly tested whether it helped to give early whole brain radiotherapy (WBRT) with chemo compared with starting with chemo alone, enrolling 176 patients with previously untreated lung cancer with brain metastases to early or delayed WBRT along with cisplatin/navelbine chemo (paper here). They found that the response rate in the brain to chemo alone, 27%, was not significantly different from the response rate to chemo with WBRT, 33%. The investigators also found that survival was just as good if you started with chemo and held off on WBRT initially.
In truth, this would represent a change from my typical practice and the approach that most oncologists follow, based largely on the old teaching, not supported by the trials, that chemo isn’t up to the task of treating brain metastases. But given the reluctance of many patients to undergo WBRT, at least without a definite need for it if chemo can provide comparable results without it, it may be worth revising our treatment approaches to get in step with the evidence.
Comparison of Iressa to Single Agent Chemo in First Line treatment for Elderly Advanced NSCLC Patients: The INVITE Trial
In addition to a direct comparison of iressa to chemo in the second line setting for advanced NSCLC (see recent post on INTEREST trial), as conducted with the INTEREST trial I described in a recent post, a very similar comparison of Iressa to chemo was also performed in another setting where single-agent chemo is also the treatment of choice. Specifically, the INVITE trial evaluated iressa vs. navelbine as a single agent in previously untreated advanced NSCLC (abstract here).
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As discussed in one of my early posts, there is room to debate whether single agent approaches or older patients should receive single-agent chemo or standard platinum-based doublets (particularly carboplatin-based instead of the more challenging cisplatin doublets). Among the most commonly used single chemo agents in the elderly population is navelbine (also known as vinorelbine), based on it being proven to improve survival compared with supportive care alone in the memorably named ELVIS trial (Elderly Lung Cancer Vinorelbine Italian Study – paper here). We’ve seen the results of a trial in which tarceva was compared to the chemo doublet of carbo/taxol in patients with a marginal performance status (not the same population as elderly), and as I described in a prior post, the recipients of chemo fared better than those who received tarceva. So did the INVITE trial show similar results for gefitinib in the elderly compared to a single chemo agent? Continue reading
The INTEREST Trial of Chemo vs. Iressa as Second Line Treatment for Advanced NSCLC
In a post several months ago, I described the results of a trial from Japan, designated V-15-32, that directly compared Iressa to Taxotere as a second line therapy. Although overall comparable, the study showed that Japanese patients receiving Iressa had a higher response rate, but despite that had a lower median and one year survival. Although Iressa overall has not shown the same degree of clinical benefit as the very similar drug Tarceva, these results were perhaps a bit surprising because EGFR inhibitors have been most effective in Asia, where a higher proportion of lung cancer patients are never-smokers and/or have an EGFR mutation. But the Japanese trial had the problem that more patients randomized to Taxotere received a potentially effective therapy (different agent with potential activity in previously treated patients) after the trial drug than patients on the Iressa arm.
One of the trials presented at the Presidential Symposium at the recent World Conference on Lung Cancer in Seoul, Korea, was called the INTEREST trial (I don’t remember what the acronym stands for, except that it was a major stretch), led in North America by my friend Ed Kim from MD Anderson Cancer Center. This trial (abstract here) had almost the exact same design as the Japanese study, again randomizing previously treated patients to either Iressa 250 mg daily or Taxotere IV every three weeks.
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The INTEREST trial was run around the world, accruing 1466 patients from 149 centers in 24 countries, making it the largest trial in previously treated patients with NSCLC that has ever been conducted. The Taxotere dose was also 75 mg/m2 every 3 weeks, the FDA-approved standard in the US based on a proven survival benefit in North American trials, while the Japanese V-15-32 trial used 60 mg/m2, which is the standard in Japan and appears to be a dose with the same general toxicity and effectiveness as a higher dose in North American/European populations. Otherwise, the INTEREST trial asked the same question as the Japanese trial but in a broader audience. Specifically, one of the reasons it was so big is that it was looking to see whether the two approaches could be proven to have the SAME survival/clinical benefit, which requires more patients than showing that one is better than another. The trial was also designed to look at whether patients with EGFR gene amplification as measured by the FISH test. Continue reading
Making Sense of the “JMDB” Trial
In my recent post on the JMDB trial that randomized patients between cisplatin/alimta and cisplatin gemcitabine in first line treatment of advanced NSCLC, the take home conclusions were that overall efficacy was very similar, with the cis/alimta arm looking a little better in several side effect parameters, most notably a less significant decline in blood counts and lower risk for fevers with a low white blood cell count. Also, the study showed the quite intriguing finding that those with adenocarcinoma and large cell tumors did signficantly better with cisplatin/alimta, while those with squamous cell carcinomas did notably (not quite statistically significantly) better with cisplatin/gemcitabine.
So a central question, first, is does this make sense? Actually, it very well might, because alimta works partly and potentially substantially by blocking a cellular enzyme called thymidylate synthase (or synthetase) (TS). There was a recent publication (abstract here) that demonstrated that levels of both messenger RNA (the code that is between the DNA and the protein it builds) and TS protein are significantly higher in squamous lung cancers than in adenocarcinomas, and also that the levels were higher in high grade cancers than lower grade ones. Higher TS levels would be expected to be associated with more resistance to alimta, while lower levels would be expected to correlate with sensitivity, as has been shown in some preclinical (lab-based) studies. Continue reading
Erbitux in Context: BMS 099 and other Trials Before FLEX
In my last post, I noted that the FLEX trial of cisplatin/navelbine with or without the EGFR monoclonal antibody erbitux was reported to be positive, demonstrating a significant survival benefit. That’s definitely going to have major implications, since our track record for phase III trials of chemo with or without new drug X was very poor for most of the last several years, until the negative streak was broken by the ECOG 4599 trial with Avastin added to carbo/taxol. Here’s the older scorecard we had:
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Not so good. EGFR inhibitors have been pretty well tested, including both Iressa and Tarceva each in two trials of more than 1000 patients randomized to chemo with or without the EGFR inhibitor, and those trials failed to show a survival benefit overall. But those agents are EGFR tyrosine kinase inhibitors, working on the inside of cancer cells, while erbitux is a monoclonal antibody that works on the outside of the cell against the same target of the EGFR molecule:
FLEX Trial of Chemo +/- Erbitux Shows Survival Benefit
Merck KgAA, the company developing cetuximab/Erbitux, the monoclonal antibody against EGFR, reviewed here) outside of the US, has announced that their pivotal FLEX trial (for First-Line Trial for patients with EGFR-Expressing Advanced NSCLC) is positive, demonstrating a signficant improvement in overall survival, as indicated here. I mentioned it as an important study to define any role for Erbitux in NSCLC, especially since a recent randomized trial I described in a prior post was reportedly negative.
The press release includes no details, just a glimpse of the trial, with a progress report last presented at ASCO 2006 (abstract here). This is a European phase III randomized trial with just over 1000 patients with previously untreated advanced NSCLC that had to have EGFR protein expression by immunohistochemistry (IHC), which is present on about 60-80% of NSCLC tumors. So there was a modest degree of selection of these patients, but a majority of patients would likely be eligible. All patients received doublet chemo with an “old school” combination of cisplatin and navelbine. This is a fine regimen but not commonly used in advanced NSCLC in the US (but still favored as a very good choice in the post-operative setting, since the majority of the best data in this setting is with cisplatin/navelbine). At the time this trial was developed, European oncologists were most commonly giving cisplatin, often with navelbine and gradually giving way in recent years to gemcitabine. Continue reading
Combinations of Proteasome Inhibitor Velcade with Chemo or Targeted Agents
Let’s move to combinations of velcade with other anti-cancer agents. My friend, Dr.Angela Davies from the University of California at Davis, led a single-arm phase II trial conducted by the Southwest Oncology Group, SWOG 0339, that evaluated the combination of velcade with gemcitabine and carboplatin (abstract here). A total of 114 patients previously untreated for advanced NSCLC were enrolled. The treatment schedule included the twice weekly schedule for velcade, so patients came in for treatment on four days over the first two weeks, followed by a week to recover blood counts:
(Click to enlarge) Continue reading
Cisplatin vs. Carboplatin for Advanced NSCLC
The question of whether to use cisplatin or carboplatin in our “platinum-based chemotherapy doublets” that are the most common treatment for the first-line treatment of NSCLC has been a smoldering debate in lung cancer for more than a decade. Although at this point carboplatin is by far and away more commonly used than the generally less tolerable cisplatin, whether these are completely identical in their efficacy isn’t entirely clear. Nobody questions that they’re very close. And the reason most oncologists feel that carboplatin is the best choice is that if there is a difference, it’s a slight one, felt to be more than offset by the toxicities and inconveniences of cisplatin compared to carboplatin, including considerably more nausea and vomiting, increased risk of kidney damage, as well as risk of hearing loss and peripheral neuropathy (nerve damage with numbness/tingling). Another factor that is important to many people is that cisplatin is administered over many hours, with lots of IV fluid support, so it usually requires either long days in the outpatient infusion center or a night or two in the hospital, while carboplatin is typically just a one-hour outpatient IV infusion.
Let’s start with one figure that is perhaps the best summary of a bleak 5 year period of lung cancer research:
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This figure of overall survival, from the ECOG 1594 trial led by Dr. Joan Schiller (abstract here), randomized over 1200 patients with previously untreated advanced NSCLC to any of 4 platinum-based chemo doublets, 3 with cisplatin and the 4th being carbo/taxol. As you can see from the figure, the survival curves for each of the four chemo combinations performed identically, with completely superimposable survival curves. This image is what oncologists think of when we consider the differences among the different platinum-based chemo doublets. They all get you to the same place.
But there have always been nagging questions about whether cisplatin may be just a shade more active. One well-publicized trial, known as TAX 326 (abstract here) and conducted by Aventis (now Sanofi-Aventis), the makers of taxotere, was very similar to ECOG 1594 in that it randomized 1219 previously untreated first-line patients with advanced NSCLC to cisplatin/navelbine, cisplatin/taxotere, or carboplatin/taxotere:
The news from this trial was that the overall survival with cisplatin/taxotere was significantly better than the “control arm” of cisplatin/navelbine. Having one doublet do significantly better than any other is pretty rare, so that’s why some people would perhaps consider the cisplatin/taxotere doublet to be among the most active combinations for NSCLC, albeit by a small margin. The carboplatin/taxotere doublet was also compared to cisplatin/navelbine and wasn’t significantly different, which isn’t a great surprise. The issue, though, is that if you try to actually compare cisplatin/taxotere to carbo/taxotere, which the trial doesn’t formally do because it was designed to just compare each of the taxotere-containing arms to cisplatin/navelbine, the carbo/taxotere arm appears notably worse: median survival of 11.3 vs. 9.4 months and one year survival 46% vs. 38%. However, this has never been highlighted.
Another trial that did directly compare cisplatin to carboplatin in a doublet with a mutual partner was conducted by Rafael Rosell and colleagues in Spain (full article here). In this trial, 618 first line NSCLC patients were randomized to cisplatin/taxol or carboplatin/taxol, and the results showed a significant survival benefit with cisplatin:
As noted in the slide on the right, there was more nausea/vomiting and kidney toxicity with cisplatin, and more of a problem with low blood counts with carboplatin. In this trial, they also measured quality of life and didn’t see any significant differences.
So as we sometimes do when we have a complex mix of studies that show varying results, a meta-analysis was performed by Ardizzoni and colleagues (abstract here) in which the investigators pooled together the results from 9 different trials that included 2968 patients who were randomized to a cisplatin- or carboplatin-containing arm of the same trial. These meta-analyses are done to give us a summary sense of what’s going on when you look across several studies that may be too small individually to detect real differences. Pooling the results of all of these cis vs. carbo studies together, the response rate with cisplatin combinations was higher (30% vs. 24%), and the overall survival benefit was 7% better with cisplatin, although that survival difference wasn’t statistically significant. In the figure below, the size of the squares represents the size of each included trial, the horizontal lines to the sides of the boxes represents the variability in the data (so long lines means very inconsistent results), and the position of the square to the right or left of the vertical line represents whether each trial showed a survival benefit for cisplatin or carboplatin, respectively:
Looking at different subsets, though, the patients with non-squamous lung cancers and those treated with the most modern chemo agents as a partner for the platinum (like the taxanes, gemcitabine, or navelbine) had a survival with cisplatin that just reached statistical significance:
Maybe that really means something, but we always want to take subset analysis with a grain of salt, because those subset analyses are sometimes done when the orignical question didn’t give you the answer you wanted, so you ask the question again 10 different ways. As the saying goes, “if you torture the data enough, eventually it’ll tell you whatever you want.” There may be something to these subsets, but the overall results are that the differences are right on the cusp of being statistically significant.
The real issue is whether the differences between cisplatin or carboplatin are clinically significant even if they are on the border of statistically significant. Some of the trials suggest a difference of perhaps a month, while others suggest less than that, in a setting where we know treatment isn’t curative. As an increasing number of drugs become available and effective in improving survival in the second and third line setting, the small differences would be expected to be diminished further: later treatments after first line chemo should be an equalizer. Now that we have the opportunity for several lines of treatment for advanced NSCLC, I am partly thinking about preserving something for round 2 and round 3 as I make recommendations for first line treatment, rather than completely beat people down by making first line treatment more toxic than it needs to be. Finally, these trials have generally included very few older and/or sicker patients, so they tend to evaluate a population that is not always representative of a “real world” patient population that would likely tolerate cisplatin as well. But perhaps these considerations sound more like rationalizations to some people.
My perspective has been that I do recommend carboplatin-based chemo for the majority of my patients in the advanced disease setting, where cisplatin can’t increase the cure rate, and the differences in efficacy are relatively small and, from my vantage point, offset by the often problematic toxicity of cisplatin, and that with the vast majority of my patients receiving later treatments, the differences in first-line treatment shoudl be smaller still. Finally, now that avastin is approved and well tested with carbo/taxol and shown to confer a significant survival benefit, this is the regimen I use for appropriate patients, and we don’t have a hint of a cisplatin combination with avastin being superior. While the combination of cisplatin/gemcitabine with avastin has been shown to be feasible and associated with an improvement in progression-free survival compared to cisplatin/gemcitabine alone (abstract here), we don’t have any data yet on overall survival with this combination, and definitely no hint it’s better than carbo/taxol/avastin.
However, I do believe in my heart of hearts that cisplatin is marginally superior, and I think this actually matters much more in the setting of curative treatment, such as adjuvant chemo after surgery or as multi-modality treatment with radiation and/or surgery for stage III NSCLC. I think if a patient can tolerate it, pushing hard and accepting greater short term (and perhaps also long-term) side effects if it can translate to a cure rate that is even a few percent higher is likely worth it. It’s possible that carboplatin-based chemo regimens are equally effective, and I’m sure they’re close, but I tend to be conservative and offer the most aggressive option that makes sense in the curative setting.
I’m changing the polling question now to see whether people would favor a more aggressive, toxic treatment for marginally better activity in the curative setting, in any setting, or whether they would prefer to accept a better balance with potentially a little less efficacy but a considerably better side effect profile. I’d love to hear what people think of this issue, not only in their poll answers, but also with any comments people have. Oncologists have been debating these issues for many years, to the point that it’s become like a “Coke vs. Pepsi” debate, but we haven’t really heard from the patients and family members most directly affected.
Maintenance Avastin after First-Line Chemo/Avastin: A Controversial Standard of Care
I’ve recently received some questions about the advantages and disadvantages of maintenance Avastin as a single agent for patients after completion of 6 cycles of first line chemo and avastin together for avastin-eligible patients. While this is generally considered to be a standard of care, many oncologists question whether it should be done. It’s worth looking at how that standard came about and the strength of the evidence for it.
The trial that led to the FDA approval of avastin was called ECOG 4599 (NEJM abstract here), and in that trial 878 patients with previously untreated advanced NSCLC (limited to those with nonsquamous cancers, no brain metastases, no history of coughing up blood, and not on coumadin or other blood thinners) were randomized to carbo/taxol for six cycles or the same chemo with avastin 15 mg/kg every three weeks. For the patients who didn’t show progression of their cancer after six cycles of chemo, the protocol had patients stop the chemo and continue on “maintenance” avastin every three weeks, until they showed evidence of progression of their disease. The trial design is as shown here:
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Described in more detail elsewhere, the trial was positive, with a significantly higher response rate, progression-free survival, and overall survival seen in the recipients of chemo with avastin:
Based on the overall survival benefit, the FDA approved avastin in this particular population, to be given with carbo/taxol, then followed by maintenance avastin. How much of the benefit was from the chemo and Avastin combination, overlapping for 6 cycles, and how much of a contribution was from the maintenance avastin? We don’t know. We just know that if you give avastin the way it was done on the ECOG trial, survival is improved, so that’s the way most experts advocate doing it. We don’t have trial results in which avastin is given with chemo but then there’s no maintenance therapy.
For what it’s worth, 53% of the patients on the trial had no progression of disease after 6 cycles of chemo/avastin and went on to receive maintenance avastin every three weeks. Half of those patients went on to receive more than 5 cycles of avastin before progressing. Importantly, some of the problematic side effects of the chemo/avastin combination, most notably the significant drops in blood counts and the associated risk of infection, pretty much went away when the chemo ended. Importantly, while we haven’t seen responses of lung cancers (or really other cancers) to avastin as a single agent, we have seen patients who had prolonged lack of progression. In a smaller trial that led to the development of the larger ECOG trial (abstract here), patients who were assigned to a chemo alone arm could cross over to high-dose avastin (15 mg/kg IV every 3 weeks) after they progressed. Of the 32 patients on the chemo alone arm, 19 received avastin. They didn’t show tumor shrinkage, but five of them went more than 6 months before showing progression, and one patient went twice as long on avastin alone without progression as he did on chemo as first line therapy before progressing (120 vs. 60 days). Here’s a survival curve in which the horizontal lines at the bottom represent the length of time that cross-over patients remained on avastin without progression:
Overall, in both the smaller phase II and the larger phase III experience, some patients went a remarkably long time before progressing, far more than you’d expect with chemo alone, yet these patients stopped chemo after 6 cycles and were maintained on avastin alone.
But what we don’t have is results of a trial in lung cancer in which patients received chemo/avastin and then no maintenance, to be compared with patients who went on to maintenance avastin (there was a European trial in colon cancer in which maintenance avastin was not included; the trial had less impressive results than expected, so some people extrapolate that the lack of maintenance avastin could be the reason). There are several potential downsides to ongoing avastin. First, there’s the cost, which if you have a significant co-payment to make, can really add up. Then there’s the safety risks, and while the decreased blood counts and infectious risks go down after chemo ends, risk of bleeding, high blood pressure, and other potentially problematic side effects can continue. And there’s the open question of whether it would be better to stop avastin after the chemo and then restart it with a new chemo or tarceva once a patient moves to a new line of treatment. Does a cancer become completely resistant to avastin, or might avastin modify the activity of many different anti-cancer drugs it’s given with? If the latter, it could be beneficial to continue it from one line of treatment to the next, the way oncologists routinely continue Herceptin for certain patients with breast cancer as they move from one chemo to another. But we have no data to answer these questions.
There are risks, there are costs, and there are potential benefits. Many oncologists are skeptical of the benefits of the maintenance avastin and think that the trial design for ECOG 4599 set up a convenient way to increase longer-term use of the very expensive avastin. It would be great to have a head-to-head trial of chemo/avastin without maintenance avastin to chemo/avastin followed by maintenance, but such a trial isn’t coming anytime soon. Until then, the majority of experts are advocating treating patients the way they were treated in the ECOG trial. But it’s possible that maintenance chemo doesn’t add much, especially if it’s restarted when a patient moves to their next line of therapy.
I’ll let you know if we learn anything more. At this point, I’m continuing with avastin and not continuing the avastin after patients have progressed and are moving on to second-line therapy.
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