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Alimta: A Newer Chemo with Increasing Utility
As I mentioned in prior posts on the topic of second-line therapy, taxotere was the first treatment approved for second-line treatment of NSCLC. Back in 2000, first-line chemo with platinum-based doublets was becoming increasingly established as demonstrating a consistent survival benefit of several months for previously untreated patients with advanced NSCLC, and then a couple of trials came out that demonstrated a modest survival benefit that for second-line taxotere, compared to either supportive care alone or compared to alternative chemotherapy (navelbine or ifosfamide). However, even after these trials demonstrated a survival benefit and taxotere was approved by the FDA for treatment as second-line therapy, only a minority of patients were getting treated in this way. A large part of this was the concern about the challenging side effects of treatment with taxotere every three weeks. Although taxotere is clearly among the most active and effective agents available for treatment of NSCLC (and many other cancers), it can cause a lot of fatigue and decreased blood counts and other problematic adverse effects. Over the last few years, the alternative approach of Alimta (also known as pemetrexed) has become available and approved by the FDA for second-line treatment of NSCLC, and it is being studied in more and more treatment settings as a potentially appealing option in lung cancer.
Alimta, or pemetrexed, is a form of standard chemotherapy that is a newer version of old standard chemo like methotrexate. These drugs are called antifolates, and they inhibit the production of critical components of DNA that growing cells need to survive. Because cancer cells are growing faster than other cells, they are particularly susceptible to the damaging effects of antifolates and can lead to death of cancer cells. The “MTA” at the end of the name Alimta stands for multi-targeted antifolate, because, as its name suggests, it actually has several targets that are critical in DNA and protein formation (too complicated and not interesting enough to go into here). In truth, the distinctions between what is called standard chemotherapy and “targeted therapy” are actually not very clear. Even regular chemo is targeted, but we have generally had a better idea of the target for the newer molecular therapies. Continue reading
Adjuvant Chemo in Older Patients: Feasible and Beneficial?
Chemotherapy after surgery has become increasingly well established as beneficial for many patients who have undergone surgery for early stage NSCLC, at least for stage II and IIIA resected disease (stage IB has had more mixed results and remains quite debatable). The chemo regimens that have been most clearly shown to confer improved survival are cisplatin-based and can have very challenging toxicity in anybody, especially after a major lung surgery. In fact, the rates of administering chemo as planned after surgery are generally about 65-75%, and this is in clinically trials that tend to enroll disproportionately younger, fitter, and more aggressively-minded patients than are seen in a broader “real world” experience. So the question of how feasible it is to administer post-operative chemo in older and potentially less robust patients is an important issue. Do such patients receive a benefit similar to that seen in younger patients, or does adjuvant chemo potentially represent treatment beyond the point of benefit that may do more harm than good? We don’t have much information, but one study presented last year provides some useful information that indicates that adjuvant chemotherapy appears to be at least of equal benefit in older compared to younger patients. Continue reading
Clinical Trial Focus: ECOG 5597 & Selenium Supplementation for Prevention?
In addition to risk for having a recurrence of a lung cancer that has been surgically removed, patients with a history of early NSCLC are also at risk for a second primary (unrelated to the first) lung cancer. In other words, having had a lung cancer, even if it was cured, means that a person remains at higher risk for a new lung cancer than people who never had a lung cancer. That risk is in the general range of about 1-1.5% per year, so patients who are around four years out from diagnosis and treatment for lung cancer are getting to a point where the risk of a recurrence is getting lower than the risk of a new cancer. Fortunately, that’s a low likelihood for both, but it’s why I and others in the lung cancer field want to continue to do approximately yearly visits and CT scans for long-term survivors of lung cancer on a chronic basis (iin addition to the surveillance function, we often genuinely LIKE the patients and are only to happy to share a hopefully upbeat, congratulatory experience). We’d all like to reduce that risk of a new lung cancer as low as possible, to get that 1-1.5% yearly risk as close to 0 as possible. But because this is a chronic, ongoing risk, any intervention/treatment that we might consider needs to have little or no toxicity if it is going to be given chronically.
Selenium is an essential (not made by the body, but needs to be consumed from the outside world) trace element in humans, which does have toxic forms, but which has been shown in some animal models to reduce the risk of some chemically-induced cancers, and it has been demonstrated to enhance immune stimulatory function in humans (reference article here). It is an essential component of the antioxidant enzyme glutathione peroxidase, which protects against oxidative damage and may possibly help stimulate the process of apoptosis (AY-pah-TOH-sis: the second p is supposed to be silent, but many people do pronounce it as AY-pop-TOH-sis), a fancy word that means “programmed cell death”, an auto-destruct mechanism that cells have built into them when they recognize that they are not functioning properly, or sometimes in normal development. One of the ways that cancers are able to succeed is that cancer cells can evade this auto-destruct mechanism. Continue reading
Lung Cancer Screening, Part III: Present and Future
Well, as I suspected, the topic of lung cancer cancer screening has been a bit of a minefield, but I’m going to end now by trying to pull together where we are here and now, at least in the US. The article about the very impressive results of the I-ELCAP trial that was published in the New England Journal of Medicine (NEJM) (abstract here) concludes that 80% of deaths from lung cancer could be prevented by CT screening and that such a screening program has a cost-effectiveness comparable to that of mammography for breast cancer. This conclusion has met with a range of views. The Lung Cancer Alliance, a national non-profit organization dedicated to patient support and advocacy for lung cancer, now recommends that higher-risk patients “should have a detailed discussion with a doctor knowledgeable about lung cancer screening on the potential risk and benefits of undergoing a baseline CT scan”. Those higher risk patients are defined as any smoker or former smoker over age 50 with a greater than 10 pack year history of smoking, or any adult with a significant exposure to cigarettes and a first-degree relative diagnosed with lung cancer before age 50, and there are some other groups, noted here, who they recommend should consider a screening discussion.
The fact that the I-ELCAP manuscript was published in NEJM certainly suggests that it is an important result that might potentially alter general practice. NEJM is arguably the most visible and influential medical journal in the world, and papers published there often change medical practice overnight. The editorial that accompanied the I-ELCAP paper noted that the survival in the large I-ELCAP trial of 88% was certainly superior to the general survival rate of 70% for stage I NSCLC at 5 years but also noted that this was an observational rather than a randomized trial, and that lead time and overdiagnosis bias could have been introduced in the survival analysis. Rather than saying that the study makes CT screening for high risk patients an appropriate new standard, or saying that these results are not adequate to change screening recommendations (which have been that there is not evidence sufficient to recommend screening), author Michael Unger called the I-ELCAP results “provocative” and left the rest of the world to fight about what this all means. No real help there. Continue reading
Lung Cancer Screening, Part II: The Downside
The topic of lung cancer screening is a very charged one, with most people, patients and physicians alike, having a strong opinion, either for or against. This is also an area in which there can be suspicion that any argument against screening is due to a financial calculation in which saving people from lung cancer isn’t worth the cost of imaging. Any screening discussion also entails a consideration of cost, financial and other, vs. benefit, but here I’ll focus on the issues related to the possible shortcomings of lung cancer screening in terms other than cost. Continue reading
Lung Cancer Screening, Part I: The Arguments FOR CT Screening
The issue of CT screening for lung cancer is a big one, and to handle it properly I’m going to write about it in a few installments. It’s also quite controversial, so today I’ll start with the reasons in favor of CT screening. Just by means of background, I’ll start by saying that chest x-rays have been studied for screening, but they don’t provide enough detail, requiring tumors to be larger before they are reliably detectable, and location of the tumor can be a problem. For instance, you can see here a chest x-ray (CXR) and a CT scan from the same patient, in whom there is really no way to find anything wrong with the CXR on the left, but the CT shows a small, well-hidden nodule (circled in red) behind the mediastinal blood vessels and other structures:
(click to enlarge)
Other relevant background information is that only approximately 25% of lung cancers are detected as stage I or II NSCLC (or about 30-35% as LD-SCLC), so most patients present with at least locally advanced NSCLC, and at least 40-50% of patients with lung cancer first have it diagnosed as advanced disease, when it cannot be cured. There is no government or medical authority that recommends routine screening for lung cancer at this time, so the current policy is essentially that you don’t start a work-up unless or until someone develops symptoms, at which time, they often have very advanced disease that has little or no chance of being cured. Here’s an unfortunate CXR appearance we see far too often at the start of a work-up:
It’s a system that leaves a lot of room for improvement. Continue reading
Stimuvax Vaccine Approach in NSCLC: Renewed Hope for Immunotherapy
Immune-based approaches in lung cancer tend to generate significant buzz among patients and the general public, as well as in the media, but not as much optimism within the oncology world. Much of that is for good reason: while the concept of a minimally toxic, long-lasting anti-cancer approach like a vaccine is very appealing to all of us, oncologists have seen many hyped immune-based therapies deliver far less than their promise. This is for several reasons. One is that cancer cells derive from normal host cells, so it can be hard to find targets on a cancer cell that aren’t also seen on normal cells. If the immunologic treatment fights normal tissues as well, it can lead to autoimmune complications. Also, many of the early studies measure success as an immune response measured on skin or in a test tube, not the more meaningful endpoints that we really care about, like tumors shrinking or people living longer. Who cares if your blood cells seem to recognize the target in a lab test, if it doesn’t translate to a patient actually doing better because of that? Also, the idea of a vaccine is generally employed before someone has the disease: you get vaccinated not when you have measles, but before you get it, so your immune system can mount a response at the first minimal threat of it. We think of immune-based therapies being most effective against a minimal tumor burden, which is not something we see enough in lung cancer, especially advanced disease. Finally, chemotherapy as well as progressing cancer can leave the body relatively immunosuppressed, so that the immune system may not have the ability to mount a strong enough response to combat a cancer meaningfully. At the end of the day, we don’t have vaccine therapies for active cancers yet. But as I write this, I wonder when I’ll need to go back to revise that statement. The FDA is considering a vaccine for advanced prostate cancer, and there are a few good leads in lung cancer as well. Today I’ll focus on L-BLP 25, now also known as Stimuvax® Continue reading
Duration of Second-Line Therapy: A Data-Free Zone
In contrast to the guidelines that exist for treating advanced lung cancer in the first-line setting for 4-6 cycles, there are really just practice patterns and good judgment to guide decisions of how long to treat in the second-line therapy. First, this is a relatively new question. As I previously mentioned when describing the history of treatment for advanced lung cancer, ten years ago there was plenty of debate about whether the benefits of treating NSCLC were sufficient to make this a standard of care. Second-line chemo for NSCLC with taxotere was first approved by the US FDA in 2000, and topotecan in 1998 for previously treated (and sensitive disease) ED-SCLC. So these are new issues. Continue reading
Optimal Duration of Therapy for First-Line Advanced Lung Cancer
The guidelines from the American Society for Clinical Oncology (ASCO) for NSCLC start the discussion on how long to continue first-line chemo as follows: “The optimal duration of chemotherapy remains a matter of debate.” Just in case you thought it was only me saying that we don’t know the exact answer for one issue or another, the evidence-based guidelines are filled with hedge comments like this. So I’ll cover what we know and what we don’t know, and how it leads most oncologists to give between 4 and 6 cycles of platinum-based doublet chemotherapy for either advanced NSCLC (“wet” stage IIIB with a malignant pleural effusion or metastatic/stage IV) or ED-SCLC. Continue reading
Chemo Combinations for Advanced NSCLC: A Regimen of Choice, or a Choice of Regimens?
We’ve come along way over the past decade. In the first half of the 1990s, the value of treating metastatic NSCLC was debated and not clear. A “meta-analysis” that pooled the results from 11 chemotherapy trials, 8 with cisplatin, and nearly 1200 patients demonstrated a modest but convincing improvement in survival compared to supportive care alone (article here). The figure summarizing the improvement by adding chemo is shown here:
(click to enlarge)
Although the difference now seems pretty convincing to me, and probably to you, at a time when treatment for advanced NSCLC was otherwise not felt to be beneficial, these results didn’t take the world by storm. Fortunately, several new drugs emerged for lung cancer that were often well tolerated and had clear activity in lung cancer as single agents:
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