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Moving Forward with Maintenance Therapy: New Trial Asking Single Agent or Combination?
The question of whether we should routinely have advanced NSCLC patients with a response or stable disease after four cycles of first line chemotherapy transition to immediate maintenance therapy or be watched during a treatment break has been the subject of several clinical trials and debates in the lung cancer community over the past couple of years. But now, with chemotherapy and the EGFR inhibitor tarceva (erlotinib) showing a survival benefit in clinical trials, we may be reaching a tipping point where the question is no longer whether to do maintenance therapy, but rather which agent or agents are the best maintenance therapy strategy. We also need to reconcile the idea of starting a new maintenance therapy with the concept of continuing a treatment from the first line setting.
The Eastern Cooperative Oncology Group (ECOG), one of the main networks of cancer centers doing collaborative cancer research together in the US, is moving ahead with a trial that aims to address some of these questions. ECOG is the network that conducted the important clinical trial (called ECOG 4599) that established the combination of carboplatin/taxol (paclitaxel) with avastin (bevacizumab) as a potential pace-setting regimen in the US after it was shown to lead to a significantly longer survival than carbo/taxol alone for patients with non-squamous advanced NSCLC. This approach entails continuing the avastin as a single agent after a fixed number of cycles of avastin with chemotherapy, typically 4-6 cycles (in the absence of progression or prohibitive side effects). At the same time, the trial of maintenance alimta (pemetrexed), previously summarized, showed a very impressive survival benefit from having patients switch to alimta after four cycles of chemo if they hadn’t progressed and were doing well.
Avastin Alone or with Alimta Following First-Line Chemotherapy: A Tale of 3 Trials
For many years, chemotherapy for advanced or metastatic NSCLC had been limited to the use of “doublet” (two-drug) therapy using different combination regimens that were overall found to have very similar outcomes, but with different toxicity (side effect) profiles. Attempts to add a third chemotherapy agent for a triplet regimen, and numerous attempts to add different targeted-therapy agents, had dismal success. Not only did most of the combinations fail to improve on the survival outcomes, they increased the number of side effects compared with doublet chemotherapy alone.
Avastin was the first targeted therapy agent to improve upon these outcomes. In a landmark phase III trial conducted by the Eastern Cooperative Oncology Group (ECOG 4599), 878 patients with advanced NSCLC received either standard-of-care carboplatin with paclitaxel, or the same doublet chemotherapy with Avastin. Due to risks of fatal bleeding in patients with squamous cell NSCLC seen in an earlier study, this trial was restricted to patients with non-squamous NSCLC. Patients received 6 cycles of chemotherapy with or without Avastin, and those on the Avastin arm then received maintenance Avastin until disease progression or intolerable toxicity.
Median survival with the doublet regimen was consistent with survival outcomes from previous studies (10.3 months), while survival for patients on the Avastin arm was significantly superior by 2 months (12.3 months). Progression-free survival (PFS, the time it takes for a cancer to start growing on chemotherapy) was also improved with the triplet, with PFS of 6.2 months compared with 4.5 months with the doublet regimen alone.
Video Presentation on Management Options for Stage IIIA NSCLC
With special thanks to the support of the Lung Cancer Connection and longtime member and friend of GRACE Myrtle Chidester, I am very happy to offer a new video podcast presentation on one of the most controversial and interesting areas of lung cancer management. Stage IIIA NSCLC with N2 mediastinal node involvement generates debates among the experts as well as at local hospital tumor boards everywhere, on a weekly basis. There is a little bit of evidence to support several views of how best to treat such patients, while in fact there is a lot of hoterogeneity within the stage IIIA N2 population. For this reason, we often manage people on a case by case basis, which may well be the optimal strategy after all.
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Lessons Learned from Maintenance Chemo Trials: My Own Interpretation
Over the past several months the topic of so-called maintenance therapy in advanced NSCLC has been one of the most timely and controversy questions in lung cancer. We’ve had posts here covering a trial testing immediate vs. delayed taxotere (docetaxel), the updated results of the maintenance alimta (pemetrexed) trial, the SATURN trial of maintenance tarceva (erlotinib), and the ATLAS trial of maintenance tarceva vs. placebo combined with maintenance avastin (bevacizumab). All of these make an argument for an immediate transition from first to second line therapy, but these studies highlight several other conclusions that we might make.
1) Treatment after first line is effective: Recommending additional treatment after the first line of therapy has been common practice for less than a decade, really becoming common practice only after taxotere was shown to improve survival (very modestly) compared with supportive care alone or alternative, less effective chemotherapy. These studies included a broad range of patients and showed rather modest survival benefits overall, actually without a clear improvement in median survival with chemotherapy.
In contrast, the maintenance therapy trials with chemotherapy have shown median survivals in the range of a year, which is much higher than the 8 month range seen in earlier second line therapy trials. Why? This is almost certainly because these trials filter out the patients who show progression, serious side effects, and/or a significant decline in their performance status over the first four cycles of first line therapy. If you remove most of the people who are likely to do poorly, you’re left with a population that is likely to do very well. We’ve never seen survival numbers like these for previously treated patients, but they’re a reflection on additional therapy being impressively effective in the patients who have stable disease or a response with first line therapy.
2) Clarification of who really benefits and who doesn’t: If we identify a group likely to benefit far more, there must also be a group who benefits much less from treatment after the first line. As noted above, the patients included in the maintenance therapy trials appear to derive a very convincing survival benefit, far more than we typically see from second line therapy in trials that enroll a broader population (including patients progressing in fewer than four cycles). This suggests that the patients with early progression receive a considerably lower magnitude of benefit from further treatment. We may do it, since the trials that included them show a modest benefit overall, but this needs to be weighed against side effects and other costs of treatment that we can’t expect to be a blockbuster.
3) Timing as “maintenance” may not matter, but treatment only helps if you get it: The main debate right now about maintenance therapy isn’t whether further treatment is valuable, but really just whether it’s critical to get it as an immediate transition from first line therapy. I don’t believe any of these trials make that argument effectively, because the trials that have shown a survival benefit (significant with alimta, a strong trend with taxotere, and an undefined but reportedly statistically significant improvement with tarceva on the SATURN trial) may well be attributable to an absolute difference in the proportion of patients on each arm who actually receive effective therapy (ever).
In the trial of immediate vs. delayed taxotere, the survival was the same when immediate treatment was compared to the subgroup of patients on the delayed taxotere arm who actually got it (which was only two thirds of the patients assigned to the delayed chemo arm). In the maintenance alimta trial, only 19% of patients on the placebo arm ever got alimta, and only two thirds got any treatment after progression, while 100% on the maintenance placebo arm got their treatment. We also know that even fewer than two thirds of the placebo recipients on the tarceva trials ever got tarceva.
So these trials aren’t really purely testing the timing of treatment as maintenance vs. waiting until progression: they’re actually testing everyone getting treatment after first line versus only about two thirds of patients getting treated. If immediate therapy isn’t pursued, the same benefit may be achieved if patients are followed diligently enough to initiate the next treatment before they experience a clinical decline.
4) Survival differences may be closely related to how many patients crossed over to the effective tretment: The maintenance therapy trial that showed the strongest survival benefit, with alimta, also had by far the lowest crossover rate to the study treatment (19%) among the people who weren’t assigned to it as maintenance therapy. We don’t know the magnitude of the overall survival benefit with the SATURN trial, but it may also reflect fewer patients on the placebo arm getting tarceva at any point.
Progression-free survival may well be the clearest and only convincing benefit with maintenance therapy, while overall survival may really reflect how many people end up receiving effective treatment after first line therapy at all. And the value of progression-free survival isn’t entirely clear if most or all patients can end up living just as long if they get start their treatment after a break.
My overall conclusion is that maintenance therapy is generally a good idea, since patients who show stable disease or a response after four cycles of first line chemo receive particularly benefit with later treatment, and whether it’s because of the timing of maintenance therapy or the fact that they actually get their intended treatment more reliable, they live longer. I don’t think every patient must get maintenance therapy, since I honestly believe that patients will do just as well if they just get their next treatment before they decline so much that they miss the opportunity.
For a minority of patients, those with a very good response and/or those with indolent disease (and most experienced oncologists can identify the general pace of a particular patient’s cancer after caring for a person and seeing the behavior of their cancer for several months), a break from treatment is likely to be perfectly appropriate. Some patients will go 3-6 months or longer before they progress, and for those patients, an immediate transition to the next line of therapy is effectively overtreatment.
So in the end, we come back to the idea that the optimal strategy is going to be an individualized approach, though I’m more likely to favor a treatment that I expect will be well tolerated as maintenance therapy in the majority of patients.
Maintenance Tarceva Trial Positive for Overall Survival Benefit
At ASCO a little over a month ago we learned the preliminary results of the SATURN trial that compared “maintenance” Tarceva (erlotinib), the oral EGFR inhibitor, to an oral placebo in patients who showed no progression after four cycles of first line chemotherapy. The results of the ASCO presentation, which showed a statistically significant improvement in progression-free survival but didn’t include any information about overall survival, are summarized in a prior post about the SATURN trial.
OSI Pharmaceuticals, the makers of Tarceva, have just put out a press release that there is also a significant improvement in overall survival among the recipients of maintenance Tarceva compared to placebo. Though no details were offered, the press release notes that more information will be presented at the upcoming World Conference on Lung Cancer in San Francisco at the end of this month. I’ll be there, so readers should expect more information as soon as the data are made public.
PET/CT Scans in Staging to Reduce “Futile Thoracotomies”
Over the lasat decade, PET scans have become commonplace in the staging of NSCLC. There’s an older post that reviews the concept of PET scans in providing metabolic imaging, as well as a podcast that provides a more complete discussion of PET scanning in oncology, with a focus on lung cancer.
A recent paper in the New England Journal of Medicine highlights the main benefit seen with PET scans for lung cancer staging. This particular paper looked at the newer combination PET/CT scans that have become very common and largely replaced separate PET scanners in many parts of the world. PET/CT scanners now allow us to see the superimposed images that provide very good detail of the shape and size of internal parts of the body (the CT portion) along with the metabolic uptake of these areas (the PET portion).
This study was conducted in Denmark and randomized 189 patients in the process of staging for possible resectable NSCLC to either conventional staging with CT-based imaging and mediastinoscopy (required) or the same treatment with a PET/CT scan. They were looking for a significant difference in the frequency of “futile thoracotomies”, so basically trying to see if PET scans cut the frequency of people undergoing a major lung surgery for no benefit. Their definition of this was rather liberal, since it included not only patients who had higher stage disease than they intended to pursue surgery on (stage IIIA with N2 nodes, stage IIIB, or stage IV), those with an unsuspected benign cause, an exploratory surgery (which I imagine would have been to determine what the cause of the lesion was), or someone who had a recurrence within a year of their surgery. This last point is a controversial one, because we might think after the surgery that a person undergoing surgery should have gotten it if their staging after surgery wasn’t too high — but if they recurred very quickly, it’s clear that these patients didn’t benefit.
Treatment of Locally-Advanced NSCLC in the Elderly: As Individualized as Medicine Gets
“Locally-advanced NSCLC” is a term generally applied to lung cancers with tumors that have either grown into major structures (such as vertebrae or spine bones, the central airways, or involve the main blood vessels supplying the lung or central chest) or those cancers that have spread to lymph nodes in the central chest (the mediastinum). In the case of many of these cancers, removing them with surgery is not possible, but treatment with the combination of chemotherapy and radiation given at the same time may be used with the goal of curing the cancer.
While administering chemotherapy and radiation at the same time (termed “concurrent therapy”) is more effective at killing cancer cells than when the treatments are given separately, this approach also causes increased side effects for the patient. Side effects may include nausea, vomiting, neutropenia (decreased levels of white blood cells which can lead to increased risk of infection) with or without infections, anemia, fatigue, and pain with swallowing (from radiation “sunburn” to the esophagus). In order for a patient to tolerate this rather stout combination, they need to be fairly healthy and active, and to have a strong physical reserve (measured with a term “performance status”).
Most studies of the combination of chemotherapy and radiation, although not excluding older patients, have enrolled younger patients. Typically, the average age of patients enrolled on trials like these is 64 or 65. This allows for decent conclusions to be drawn for patients of this age group and younger, but how do these studies apply to the elderly; patients 75, 80, older?
Interview with Dr. Sarita Dubey on Chemo for Early Stage NSCLC
Here’s an interview I did a few weeks before ASCO with Dr. Sarita Dubey, medical oncologist at the University of California at San Francisco. This podcast covers a discussion we had about her views on the role of chemotherapy for patients with resected or resectable early stage NSCLC.
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Congratulations, your tumor is stable! So… is that good news or bad news?
There is nothing more disheartening to the patient, and quite frankly for the treating oncologist, than have to hear (or say) the words “I’m afraid the treatment isn’t working”. The scientific term is “disease progression”, but the reality is that the cancer is growing despite the treatment and it doesn’t take an expert to know that isn’t good news.
However, next in line in the statements that seem to generate a decided lack of enthusiasm is “Your cancer is stable”. Stable doesn’t sound so bad, does it? The tumors haven’t changed, nothing is growing, there are no new lesions to suggest progression, but all of these reassurances often seem to fall on deaf ears. Sure, we’ll keep going with the treatment, but it MUST be bad that the tumors didn’t shrink, right? I sometimes think my patients feel I’m being dishonest with them when I get enthusiastic about something as ambiguous as disease stability.
Of course, it isn’t hard to understand this feeling. Who wouldn’t want a clear sign that the cancer is dying, that the treatment is working. Patients want their cancer to be gone, and watching it disappear must be very heartening. I also admit that there is little in my job as gratifying as looking over the scan and seeing that the tumors have all shrunk, what is known as an “objective response”. I’ll often pull this type of scan up on the exam room computer to show off my treatment prowess: look at what I did! But is a response really that important?
Let’s look at tumor responses for a minute. If the tumors shrink but don’t disappear this is called a “partial response” (or PR) and if they disappear entirely this is called a “complete response” or (CR). Response rates have been the traditional marker of whether a chemotherapy drug is effective, and historically drugs that did not cause tumors to shrink have been abandoned. Stable disease (SD) was usually reported separately, if at all, and has been regarded by some as the poor man’s response rate. If your trial failed and there were no responses, at least you can report a high SD rate and maybe someone will think your drug is good for something!
But this concept has changed a lot in the modern era. Trials utilizing so-called “targeted agents” have even reported improvements in overall survival with few or any objective tumor responses. One good example of this is the randomized trial of Nexavar (sorafenib) in hepatocellular (liver) cancer. This trial showed a 3 month improvement in overall survival in patients with HCC treated with sorafenib, despite only 2% of patients “responding” to the drug. Trials like this one have raised the question of just how important response rate is to determining if a drug is helpful or not.
But that was for these new, fancy-schmancy drugs like Nexavar or Tarceva. What about ordinary chemotherapy? Well, at the 2009 ASCO meeting in Orlando there was a poster that I found fascinating but I haven’t heard too much buzz about. A group of investigators from Japan, led by Dr. Hirokazu Watanabe, looked at the survival of advanced NSCLC patients treated with 4 different platinum-based chemo regimens as part of a clinical trial and related the survival to whether the patients had a response, stable disease, or progressive disease as their best outcome. Continue reading
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