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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
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:
Early Disease Control: More Predictive of Clinical Benefit than Response
In my last post, I described our evolving recognition in the lung cancer field that significant response as the threshold for clinical benefit is too high and that stable disease is likely a relative benefit as well. An important trial presented by Dr. Lara at UC Davis at ASCO (our biggest cancer meeting) in June, 2006 (abstract here) highlighted not only that or disease control rate (DCR), or “non-progression” is more predictive of improved survival outcomes than response rate (RR), and that the prediction can be made reliably in the second month after starting treatment, usually after two cycles of chemo (I recently wrote about early follow-up PET scans to predict outcome in advanced NSCLC, but a CT scan after two cycles of chemo is much more commonly practiced).
Obviously, disease stage is the most important factor in predicting survival in cancer patients. Staging is designed to separate anticipated survival into various groups. But when I meet new patients just starting on therapy, I tell them that the second key piece of information that we don’t have yet is how responsive their cancer is. Dr. Lara’s study demonstrates that we can get a good idea of longer term outcomes within the first couple of months, and that the survival of patients with stable disease is closer to that of responders than that of progressors. Continue reading
Treatment of Recurrent SCLC: Evidence for Survival Benefit
As I mentioned in my introduction to the topic, SCLC is typically sensitive to chemo and radiation initially, but it tends to be considerably less responsive after recurrence. Unfortunately, most SCLC patients, or about 75-80% of patients with LD-SCLC and nearly 100% of patients with ED-SCLC , do subsequently recur. One key theme is that the longer patients go between ending first-line treatment and developing a recurrence, the better they are likely to do with any treatment. Such patients are generally divided into those with “resistant” or “sensitive” disease, depending on whether recurrence occurs before or after a 2-3 month period (some define the break point at 2 months, others at 3). It is felt that since initial chemo effectively treats the sensitive disease, the time before recurrence essentially measures the proportion of sensitive vs. resistant cancer cells. Oncologists have generally found the treatments for resistant SCLC to be minimally effective (fewer than 10% of patients respond), but even for more sensitive SCLC (where response rates can be in the 30-40% range in some trials), we have not had good evidence that patients receive significant benefit compared with the side effects. Many patients are in pretty marginal condition for more treatment, and the benefits have appeared to be modest. Accumulating evidence, however, now supports single-agent chemo, most often with topotecan/Hycamtin, and a just reported trial shows a significant improvement in survival compared to supportive care alone. Continue reading
Mediastinal N2 Lymph Nodes after Induction Therapy as a Key Predictor of Outcome
For patients with locally advanced NSCLC, the question of whether to pursue a surgical or a non-surgical approach has a great deal to do with the extent of mediastinal (middle of the chest) lymph node involvement. The mediastinal nodes are shown here:
(click to enlarge)
First, at the time of initial staging, patients with bulky (>3 cm) disease in the mediastinum, or those with disease involvement more than one nodal station, are less appropriate candidates for surgery than those with non-bulky and single-station disease. In fact, a French retrospective review of over 700 patients with N2 disease who underwent surgery at any of six centers (Andre abstract here) demonstrated that there are quite varied long-term outcomes for different patients that all fall under the same stage of IIIA with N2 disease, and that the patients with a single-station and microscopic involvement (as opposed to clinical enlargement that is visible as abnormal on CT (greater than 1 cm in diameter):
That was in a group of patients who underwent surgery, and just a view of how patients did after the fact. Continue reading
Pushing the Envelope: Surgery after Full Dose Radiation with Chemo
As I described in a prior post, pre-operative chemo and radiation are one very reasonable, aggressive option for stage IIIA NSCLC, particularly if the mediastinal lymph nodes involved are not large and there is only a single lymph node area involved. However, the radiation that is generally used before surgery is about 45-50 Gray (Gy) over about 5 weeks, not the “definitive” radiation dose we use if we aren’t planning to pursue surgery, which is more like 61-66 Gy at most centers. We have not generally given full dose radation followed by surgery, out of concern for the difficulty of surgery in a heavily radiated, scarred field, and the risk of severe complications after that. However, in unusual cases we have pursued that option, sometimes with very good results, and the concept has also been the subject of published work. Continue reading
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