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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
Treating Elderly and Poorer Performance Status Patients with Small Cell Lung Cancer
The fact is that lung cancer, like many others, is a disease disproportionately affecting older populations, with the median age now in the 69-70 range.
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But our trials in lung cancer only rarely involve patients over 70. This leaves us with serious questions about the best way to treat older and poor performance status patients. It’s also important to note that elderly doesn’t mean poor performance status. There are remarkably healthy older patients, now more than ever, and there are also debilitated patients under 70 as well:
But a lot of patients with SCLC are elderly and/or frail when they present for treatment, and the question is whether they should be treated the same as younger patients or whether plans should be modified. Continue reading
Cisplatin vs. Carboplatin in Small Cell Lung Cancer
I recently received a question on the Q&A Forum about the use of cisplatin vs. carboplatin in SCLC. In contrast to the smoldering debate about cisplatin vs. carboplatin in NSCLC that I described in a recent post, there’s been very little study and not as much debate about SCLC. What little I can say is that there was a trial published in 1994 by Skarlos and colleagues from Greece that randomized patients to cisplatin or carboplatin with etoposide, and it included patients with both limited and extensive SCLC (abstract here):
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This trial is so old that the carboplatin dose is in mg/m2, which is an older way of dosing this agent than our current one that uses age, patient sex, and kidney function to calculate a drug exposure known as area under the curve, or AUC. Our current dosing of carboplatin is almost always by AUC. And just FYI, the dose of etoposide listed on my figure is different from the one listed in the abstract. I believe the latter is a typo/misprint, but I don’t have the original paper availabel to double check that. The dose of 300 mg/m2 would be a staggeringly high dose, at least if we’re talking IV and not oral etoposide.
The study demonstrated relarkably similar results for the two arms, with very impressive complete response rates of 57% and 58% and median survivals of 12.5 and 11.8 months for cisplatin and carboplatin, respectively. The toxicity profile favored carboplatin, with significantly lower rates of severe nausea/vomiting, neurotoxicity (neuropathy), and leukopenia (low white blood cell counts), and infections in the patients who received carboplatin. So this work suggests comparable results and perhaps a more favorable therapeutic index (balance of activity vs. side effects) for carboplatin.
That’s one reason I modestly favor carboplatin over cisplatin outside of a clinical trial in ED-SCLC. Many additional trials have been done with carboplatin-based chemo in ED-SCLC that show survival about what you’d expect for cisplatin as well, and I’ll soon give some additional information on one trial presented at ASCO 2007 that compared two carboplatin-based doublet regimens.
However, in a curative setting like LD-SCLC, I still favor cisplatin. There are no places in oncology where cure rates are better with carboplatin than cisplatin, but there are a number where cisplatin is signficantly (if modestly) better than carboplatin. In fact, the full paper showed some trends that looked a little worse for carboplatin recipients LD-SCLC, but the trial is small, and the differences weren’t enough to be statistically significant. Given the high stakes and the much more extensive body of evidence with cisplatin in LD-SCLC (the best data we have in long-term cure rates in LD-SCLC are with cisplatin/etoposide and twice daily RT, as described in a prior post), that’s my standard approach unless there’s a reason a patient can’t tolerate cisplatin. At least we have some evidence to suggest that patients who get carboplatin instead of cisplatin aren’t compromising significantly and may do just as well, based on this limited Greek experience.
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.
Is There a Better Way to Combine EGFR Inhibitors and Chemo? The Concept of Pharmacodynamic Separation
Our tendency in oncology is that once we find a new active drug in cancer, we try to add it to our current standard treatment approach and see if we can do better than what our current standard achieves. More is better. And we knew that the epidermal growth factor receptor inhibitors Iressa and Tarceva could lead to significant shrinkage of some lung cancers. So the lung cancer community was relatively optimistic about the clinical trials that compared chemo alone to the same chemo with Iressa or Tarceva. In fact, each EGFR inhibitor was studied in two different first-line trials, one each with carbo/taxol, for a primarily US-based experience, and also cisplatin/gemcitabine, a common standard for much of the rest of the world. Of these four trials, each with over 1000 patients, the overall results showed no benefit with the addition of either EGFR inhibitor:
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So how could we add two active anti-cancer approaches and not get any additional benefit? One idea is that perhaps we looked at the wrong group, that we should use targeted therapies in a targeted way. We did see encouraging results in the never-smokers on the TRIBUTE trial, who had a more than doubling of their median survival when tarceva was added to carbo/taxol:
As I described extensively in my prior post about why I don’t give chemo and EGFR inhibitors concurrently, I think those results are encouraging, but I’m struck by the fact that the tarceva arm really seems to start doing better several months into the trial, right around the time when they’d be finishing the planned 6 cycles of chemo. So to me it seems that the never-smoker tarceva recipients did well despite receiving chemo and tarceva concurrently, because they really come into their own when the chemo is over (arrows added for the approximate time when 6 cycles of chemo would end):
Carboplatin/Alimta for Mesothelioma, or NSCLC
So far, I’ve only written a few introductory posts on mesothelioma, but there were some interesting presentations at ASCO 2007 about the topic. One described the results of an expanded access protocol (EAP), which is when a company gives free access to a drug that is not yet commercially available (generally in exchange for participation in a data-collection study). This EAP was for Alimta (pemetrexed) as a treatment for malignant pleural mesothelioma (MPM) in Europe (abstract here). On this EAP, patients with mesothelioma from 13 different European countries were enrolled and could receive cisplatin/alimta (the combination approved by the FDA after being studied in a large randomized trial (abstract here)), carboplatin/alimta (carbo being a popular substitution for cisplatin in many settings because it is associated with considerably less nausea, risk of kidney damage, hearing loss, and some other side effects), or alimta alone. All patients received B12 and folate supplementation with their chemo. Over 3000 patients with MPM had data collected on how they tolerated treatment and how well they did on therapy, with just over 2000 of them receiving this treatment as their first chemotherapy. The report described the experiences of the 1704 patients who received alimta with either cisplatin or carboplatin, rather than alimta alone, and compared the results. The groups were almost evenly split between the two combinations (843 getting cis/alimta, 861 getting carbo/alimta). The two groups were quite comparable except that the median age of patients getting carboplatin was about 66, vs. 62 for recipients of cisplatin. This isn’t especially surprising, because the younger, presumably a little healthier patients would likely be selected to receive the more rigorous treatment.
The results showed that the two groups performed remarkably similarly in just about every way. The median number of cycles was 5 with cis/alimta vs. 6 with carboplatin/alimta, but otherwise, both groups had the same general response rate in the 25% range, the same disease control rate (stable or responding) of 75-80%, median time to progression of 7 months, and one-year survival rate of 60-65%. Looking at the numbers and the survival curves, it’s impressive to see how overlapping they really were:
(Click to enlarge) Continue reading
Older Women with NSCLC Do Better: An Increasingly Consistent Finding
Over the past few years, sex-based differences in lung cancer have become increasingly recognized as relevant in prognosis overall and potentially in predicting response to treatment, such as EGFR inhibitors and other targeted therapies. At ASCO 2007, a group led by Dr. Kathy Albain, long committed to learning more about sex differences in lung cancer outcomes, presented a review of results from a series of six recent chemotherapy-based trials conducted by the Southwest Oncology Group (SWOG) in the setting of advanced NSCLC, divided by patient sex (abstract here):
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Among the 1334 patients enrolled in these six trials, 36% were women; having women under-represented on lung cancer trials is unfortunately typical (although better than it used to be in the US, and still much better than in European trials, where women constitute just 10-15% of patients in some studies). Women and men didn’t differ in their characteristics going into the trial, such as age, performance status, and stage, but women were a little less likely to have weight loss of 5% of baseline weight or more compared to men (33% vs 41%).
Despite starting out with the same characteristics as the men and experiencing a very similar range and severity of treatment-related side effects as men, women had a significantly better overall survival than men, with a median survival of 11 vs. 8 months, a one year survival of 46% vs. 35%, and a two-year survival of 19% vs. 13% (P = 0.02 for the entire overall survival analysis by sex):
But it really wasn’t all women. Instead, the better survival was limited to women over 60, while women and men under 60 had a very similar survival:
That may sound surprising, but we’re seeing more and more that hormonal differences may be pretty important. Next I’ll describe some of the mounting evidence that is converging to show that women with high serum estradiol levels (a premenopausal picture) don’t do as well as women with low serum estradiol levels most commonly seen in older, post-menopausal women.
The Latest on Induction Chemo for Stage III NSCLC: More is Not Better
As a follow-up to my last post and an end to this extended discusison of locally advanced NSCLC before moving to other topics, I’ll just cover some more recent work on the topic of chemo followed by chemo and radiation for stage III NSCLC. In that post, I showed that over the past several years, we hadn’t seen the promise of this induction strategy in small trials translate into especially favorable results in larger multicenter trials.
More recently, we’ve seen the CALGB continue to study this approach, in trial 39801, presented by Dr. Everett Vokes from the University of Chicago at ASCO several years ago and then published very recently (abstract here). This trial really directly tested the value of induction chemo, because the trial randomized just over 360 patients with unresectable stage III NSCLC to either weekly carbo/taxol and concurrent RT for 7 weeks, or two cycles of carbo/taxol (one day every three weeks at a higher dose) followed by the same weekly chemo and concurrent RT. The trial showed no significant differences between the two arms, no improvement in survival, progression-free survival, or distant failures (which we might presume would be lower with the induction chemo strategy, because I had previously mentioned that many of us are concerned that low-dose weekly carbo/taxol may not treat micrometastases effectively). These results indicated that adding the higher doses of chemo didn’t add anything but more side effects, which included significantly more low white blood cell counts and more pneumonitis (inflammation of the lung tissue). Here’s the summary of the trial:
At the time of his initial presentation of the trial at ASCO a couple of years ago, Dr. Vokes noted that the 12-14 month median overall survival was pretty disappointing, and he raised the question of whether that might be because a carboplatin-based regimen was used instead of a cisplatin-based regimen, since trials in stage III NSCLC that use cisplatin-based chemo and RT together have recently shown median survivals in the 19-21 month range. I think there’s a real possibility that this is the case, but some others have suggested that the lower survival is because somewhat less fit patients were channeled into this trial than the cisplatin-based trials. Some of the investigators were concerned that just seven weeks of low-dose carbo/taxol with RT wouldn’t be enough chemo treatment, so more marginal performance status patients went on this trial, while the healthier ones might have been directed to more aggressive approaches. So here’s an example where selection bias may have led to lower survivals than you would otherwise expect. However, I still prefer to give cisplatin-based chemo in the curative setting, if the patient can tolerate it.
Another trial presented at ASCO 2007 by Kim and colleagues from Korea also tested induction therapy (abstract here). This study enrolled 134 stage III NSCLC patients who either received cisplatin/taxol and concurrent RT for 6 weeks with no other treatment, or two cycles of cisplatin/gemcitabine as induction chemo, followed by the same cisplatin/taxol and RT:
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It’s not a large trial, but it showed no hint of benefit for the induction approach. In fact, the induction chemotherapy arm had a significantly worse progression-free survival and a strong trend toward a worse overall survival:
Why would that happen? Potentially because they saw the same trend that I described with the LAMP trial in my last post: the patients who went from chemo to chemoradiation had a much harder time getting through all of their planned chemoradiation, with only 69% of patients getting all six cycles of chemo with RT in the group starting with induction chemo, vs. 86% in the group that just did concurrent chemoradiation.
So that’s where we are. No hard evidence that additional chemo before or after a mere 6-7 weeks of chemo with RT improves survival. I suspect that part of the problem is that this is challenging treatment, and it’s a point where people can be limited by the side effects of treatment pretty readily when their performance status isn’t great and the treatment is rough. I believe it’s quite possible that the fittest patients may do better to get more chemo, but those struggling to just get through 6-7 weeks of chemo/RT together may be better served by concentrating on the highest yield treatment and avoiding treatments that push them into the danger zone where treatment can be as threatening as the disease. But in the meantime, I’ve taken a step back from my presumptions and now can say just that my preference is for two cycles, or about 6 weeks worth, of cisplatin-based chemo, and concurrent RT. The rest may not buy you much, if anything.
Next we shift to something different, a new approach to personalizing cancer treatments.
Induction Chemo before Chemo/Radiation for Stage III NSCLC: Is Earlier Better?
The last topic in our discussion of the evolving field of optimal treatment for locally advanced NSCLC is the potential role for induction chemotherapy before radiation, or, more commonly concurrent chemo/radiation (CT/RT). In my recent post, we covered the new findings from ASCO 2007 that our common practice of giving concurrent CT/RT followed by consolidation chemo, most commonly with taxotere, is not necessarily the best treatment for most patients with unresectable stage III NSCLC. Perhaps giving chemo before the concurrent CT/RT is a better approach. After all, the trial that established a role for chemo in stage III NSCLC back in 1990 first gave chemo, followed by radiation (summarized in another recent post).
Since then, while some investigators have used the SWOG approach of initial CT/RT followed by more chemo, others have used the reverse, starting with chemo and then continuing on to concurrent CT/RT. Some of these trials have been pretty promising. Dr. Everett Vokes, who chairs the Lung Cancer Committee for the Cancer and Leukemia Group B (CALGB) published a trial that gave two cycles of cisplatin with any of three different partner drugs — taxol, navelbine, or gemcitabine — followed by the same combination at lower doses with concurrent chest RT (abstract here). The trial was designed as shown, and as you can see from the results slide, all three of these combinations performed similarly, although there was a lot of toxicity when gemcitabine was combined with radiation (at the time it wasn’t known how extremely radiosensitizing gemcitabine is). Here’s the trial design and results:
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Those results are all pretty good. Another trial, done by Dr. Mark Socinski and his colleagues at the University of North Carolina (abstract here), gave two cycles of carbo/taxol followed by weekly carbo/taxol along with concurrent RT to an escalating dose, beyond the typical 60 Gray (Gy) range and all the way up to 74 Gy (they’re very good at radiation therapy there and do a lot of pioneering work at UNC):
The results looked quite impressive, with 40% of patients on the trial alive three years later, but this was a single institution trial with just 62 patients. We’d need to see how something similar to this approach works in the real world, with more participating centers. Continue reading
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