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Pre-operative Chemotherapy for Early Stage NSCLC?
Over the last several years, chemotherapy after surgery has become the standard strategy for improving survival compared to surgery alone, at least for stage II and IIIA patients who don’t have mediastinal (N2) lymph nodes involved, and it’s often used also for patients with stage IB NSCLC (no lymph nodes, but a larger tumor or tumor involvement with the pleural lining around the lung). However, another approach that has been studied, albeit less so than adjuvant (post-operative) chemotherapy is neoadjuvant (pre-operative, also known as induction) chemotherapy. This strategy has several potential advantages over administering chemo after surgery. First, when we’re trying to improve survival with chemo by treating potential micrometastases, neoadjuvant chemotherapy has the potential to start treating these micrometastases at the earliest possible time. In addition, chemotherapy before surgery can allow us to assess how responsive the cancer is to treatment, in a way that post-operative chemo cannot. We can see how much the tumor shrank on repeat CT scans (+/- PET scans), and we can look at changes in the tumor itself after it has been removed at surgery. Perhaps more importantly, there is the potential that in patients who have a tumor that may require a more extensive surgery such as a bilobectomy (lwo right-sided lobes) or pneumonectomy (full lung resected), it may be possible to shrink the tumor enough before surgery to do a lobectomy (in fact, people still debate whether you should do the surgery that was needed before the induction therapy, or whether you can do surgery and just remove the area that it shrunk to. This is really a question of whether there are residual “islands” of viable tumor outside of the newly shrunken borders of a tumor after treatment). It is also possible to identify a small minority of patinets who progress immediately, despite treatment, which happens perhaps 5-10% of the time. In those patients who develop progression with metastases before getting to surgery, you could consider them as having lost the chance for cure with surgery, but we really think these are the patients who would have shown progression immediately after surgery if they had gone straight to the operating room, so they have probably been spared a surgery that would not have helped them.
But the leading reason that we would consider pre-operative chemotherapy to be potentially more helpful than post-operative chemo is that we think you can get it in more reliably. One of the biggest problems with adjuvant chemo is that patients are just recovering from a MAJOR surgery, and many have recently lost a bunch of weight, they’re in pain, they’re constipated because of their pain meds, or any of many other problems people can have after major surgery. They may not be able to get through a challenging plan for 3-4 cycles of chemo, since chemo isn’t exactly a cake walk even for people who didn’t just have major surgery. The trials of adjuvant chemo, which only included the patients motivated and fit enough after surgery to consider chemo (which definitely isn’t every patient), have consistently shown that only about two thirds can get through the majority of planned treatment:
(click to enlarge) Continue reading
Amrubicin Looking Promising in Recurrent SCLC
Small cell lung cancer (SCLC) has been a very challenging disease for patients and physicians, and unfortunately one in which our improvements in treatment have been few and far between. In fact, a recent educational session at ASCO was titled “Small Cell Lung Cancer: What’s New Since 1978?”. The decreasing frequency of SCLC has also made it increasingly difficult to study, but even when the studies are completed, many emerging potential therapies have proven to have no benefit.
But there is a glimmer of hope on the horizon. A drug called amrubicin, which is a type of chemo drug called an anthracycline, with multiple DNA damaging effects on cells. Amrubicin is metabolized to amrubicinol, an active metabolite with 5-200 times the inhibitory effect of the original drug.
(click to enlarge) Continue reading
The Value of Surgery for Brain Metastases
I briefly mentioned the potential value of surgery for a solitary brain metastasis, where it is commonly used, in another post. Today I’ll talk more specifically about where the role for surgery has been specifically tested for brain metastases in lung cancer. Aside from possibly removing the only lesion (in certain cases, where it can be associated with long-term survival, as I described in my post on solitary brain metastases), neurosurgery is used to offer rapid relief of symptoms resulting from the mass effect of a large tumor, to improve local control of brain metastases, and/or to clarify the tissue diagnosis when there is some question about the underlying diagnosis of a brain lesion. Improvements in anesthesia and neurosurgery have made this intervention safer and more feasible for patients over time.
One way to assess the value of surgery in the treatment of brain metastases is by comparing the results of WBRT vs. a combination of neurosurgery and SRS, and three randomized trials have done that (abstracts here and here and here). The first was an influential trial by Patchell and colleagues (abstract here), of 48 patients with a single brain metastasis who underwent surgery followed within two weeks by WBRT (36 Gy over 12 fractions) or WBRT alone. This study, although small, did show very clear and statistically significant improvements in likelihood of recurrence of brain metastases (20% vs. 52%) and median overal survival (40 vs. 15 wks). These results were corroborated by another trial (abstract here) of 63 patients with a single brain lesion who received WBRT alone or preceded by surgery, showing a significant improvement in survival (10 vs. 6 months). These trials both also showed that patients undergoing a combination of surgery and WBRT remained functionally independent for longer. The third and largest trial (abstract here), with 84 patients who also had a single brain lesion, actually did not demonstrate a significant improvement in survival or functional status, but this trial had patients with a greater burden of distant disease than the other trials. The results of these three studies are shown here:
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The differences among these trials reminds us that the value of surgery for brain metastases is still questionable, and it is a most compelling consideration for patients with a single metastasis, good performance status, and controlled disease outside of the brain. There is really remarkably little experience to guide us on the value of surgery for more than a solitary brain metastasis, but it is generally felt to be far less appealing than in the more commonly advocated setting of treating a single brain metastasis.
Motexafin Gadolinium (Xcytrin) with WBRT for Brain Metastases?
A novel agent called motexafin gadolinium (MGd), with a marketed name of Xcytrin, has been studied as a potential neuroprotectant as well as radiosensitizer that may allow patients with brain metastases to do better when it as added to whole brain radiation therapy (WBRT) than they would with WBRT alone. It is a molecule called a metallotexaphyrin, which forms stable complexes with large metal cations and accumulates preferentially in tumor cells (reference abstract here). It is readily detectable by MRI, and in fact some have suggested that no matter what else it may do, it could be a remarkably sensitive tool for picking up brain metastases. Here is an example of how good is is at identifying metastases on a brain MRI, and how well it localizes in brain tumor tissue:
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It inhibits an enzyme called thioredoxin reductase, which can be overexpressed in lung cancer, in which it is associated with aggressive disease, tumor resistance, and worse survival. MGd generates reactive oxygen species by catalyzing the oxidation of several intracellular-reducing metabolites, which leads to radiosensitization (stronger effects of radiation)(abstract here). Continue reading
Tarceva Drug and Food Interactions
Before turning back to brain metastases, I wanted to cover a topic that has generated some recent questions, and that is the issue of potential interactions of tarceva with food and other drugs. Just as an introduction, the standard dose of single-agent tarceva in lung cancer is 150 mg by mouth daily, and this is meant to be taken on an empty stomach, at least one-hour before or two hours after eating. Taking tarceva with food can make the absorption of tarceva greater but is overall so variable that it’s very hard to know what kind of blood levels to expect, so the established target is 150 mg taken on an empty stomach. Tarceva is broken down by a collection of liver enzymes known as the CYP (pronounced “sip”) family, and particularly a liver enzyme known as CYP 3A4. These enzymes can also be found in the intestinal lining and can affect absorption of drugs like Tarceva. The CYP enzymes, and particularly CYP 3A4, can have their levels affected by other medicines and foods. Interestingly, tobacco smoking is another factor that can increase clearance of tarceva: in active smokers, tarceva clearance is about 25% faster, so the blood levels are lower. The potential that tarceva may need a different dose level for active (not likely former) smokers is a question that needs to be addressed further, and one I’ll have to cover in a separate post.
The medicines that inhibit CYP 3A4 can dramatically increase levels of tarceva. These are drugs like ketoconazole, an antifungal medicine, and other antifungal and antiviral drugs, including several used to treat HIV/AIDS. Grapefruit juice also inhibits CYP3A4. Any of these agents can decrease tarceva clearance by about 2/3, so reducing the dose of tarceva should be considered, particularly if a patient is experiencing significant tarceva-related side effects.
On the flipside, a bunch of other medicines can significantly increase CYP3A4 activity and reduce tarceva levels by about 2/3. These include an antibiotic called rifampin, multiple anti-epilepsy drugs (including dilantin, tegretol, and phenobarbital), and St. John’s Wort. One recommendation in the tarceva product information is to not take these other drugs if there is a possible alternative, but otherwise, it is recommended that a higher dose than 150 mg daily be considered. In fact, studies of patients with primary brain tumors, who often need to be on anti-convulsant drugs like dilantin, have demontrasted that higher doses of 300 mg or even up to 500 mg daily are safe (abstract here), and that the 500 mg daily dose in someone on a CYP 3A4 inducing-drug like dilantin is associated with tarceva blood levels similar to the 150 mg dose in someone who isn’t on one of these CYP 3A4 inducers (abstract here). While there isn’t an official recommendation to prescribe a higher dose, the FDA acknowledges that this is something that should be considered for patients on drugs that are known to increase tarceva clearance. Continue reading
COX-2 Inhibition Combined with Chemo for NSCLC
Celecoxib (Celebrex) has been studied in combination with chemo for NSCLC and has generated enough promising results to raise expectations but also enough negative data to produce disappointment. Dr. Altorki’s trial (abstract here) gave 29 patients with stage IIIA, resectable NSCLC celebrex at 400 mg by mouth twice daily (higher than standard arthritis dosing, but the dose used to reverse colon polyps in patients with a high risk pre-malignant condition for colon cancer called familial adenomatous polyposis, or FAP) along with two cycles of carbo/taxol every three weeks as an induction therapy. It showed a good response rate (tumor shrinkage by 50% or more) of 65% (17% with a “complete response” (CR) of no residual disease visible on CT scans, and 48% with significant shrinkage but residual disease seen). The greatest encouragement came from the 24% of patients who had a “near pathologic CR” in which there was just a small focus of residual disease seen on the microscopic review of tissue after surgery. This was viewed as particularly encouraging since we expect the complete pathologic CR rate to be only perhaps 5-10%, but I must admit that I was less enthralled by this statistic, since no prior studies ever reported a “near pathologic CR” with just slight residual disease, and for all we knew, many other trials had 20-50% near pathologic CRs but never reported them. To me this seemed like being just a little pregnant if the real victory is NO cancer visible under the microscope. Continue reading
COX-2 Inhibitor Therapy: Potential Relevance as Cancer Treatment?
We’ll break from brain metastases for a while to talk about another potential avenue of targeted therapy in lung cancer: the cyclo-oxygenase, or COX, pathway.
Cyclo-oxygenase (COX) inhibition has been studied as a potential mechanism for inhibiting cancer over the past few years, and recently some early clinical trial results have looked promising and generated a great deal of enthusiasm. A central component of the arachadonic acid pathway (complicated, and not on the quiz, so don’t worry about it unless very motivated), COX is an enzyme found in two common forms, COX-1 and COX-2. COX-1 is constitutively expressed, which means it is present routinely in normal cells and plays a part in many routine cellular functions, among them helping to maintain the gastrointestinal (GI) mucosa. In contrast, COX-2 is an inducible enzyme, meaning that it is expressed selectively in the setting of signals that trigger inflammation as well as cancer development. Non-steroidal anti-inflammatory drugs (NSAIDs), your basic naproxen or ibuprofen, block both COX-1 and COX-2, and they can effectively reduce pain in the setting of inflammation, which is why they are taken for back pain and muscle aches, etc. Unfortunately, they can block some of the normal activities of platelets, which are important in clotting when you need to, and they can harm the stomach lining and lead to ulcers (remember that COX-1 helps maintain the stomach lining) and GI bleeding, which is uncommon but definitely seen with NSAIDs. COX-2 inhibitors, in contrast, have the potential to block inflammatory effects without the detrimental effects on platelet function or stomach lining. Here’s a pretty detailed diagram:
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As you probably know from watching the news in the last few years, COX-2 inhibitors don’t appear to be toxicity-free, either. Rofecoxib (Vioxx) was taken off of the US market after initial FDA approval based on findings of increased cardiac events (summarized here), and there have also been reports about similar increases in cardiovascular events among people who received celecoxib (Celebrex) (abstract here).
Why are we talking about medicines for musculoskeletal pain here? Because COX-2 may be relevant in the development of, and treatment of, cancer. For starters, I mentioned that it isn’t seen in normal tissues, but it’s present on many different types of cancers, including NSCLC.
Solitary Brain Mets and the Concept of the “Precocious Metastasis”: A Special Case
We’ll cover the general management principles for the more typical situation of patients with multiple brain metastases from lung cancer soon, but today we’ll cover the special situation of the patient who has a brain metastasis identified as the ONLY area of metastatic disease (generally referring to NSCLC, since SCLC has such a high tendency to spread distantly early in its history). Recall that metastatic, or stage IV, lung cancer, is treated with a palliative approach, due to the inability to achieve prolonged survival except in very rare cases. These patients are generally treated as a unique category for whom an aggressive treatment is often considered, not only for the brain metastasis but also for disease in the chest.
One important point is that finding an area of metastatic disease in the brain only represents the concept of a “precocious metastasis”, a metastatic deposit that somehow slipped out before the rest of the disease was readily shedding metastatic disease (not all of the discussion of this concept requires just a single brain metastasis – some consider this idea to also apply to up to three brain lesions that can be treated aggressively). A thorough staging workup, including a PET scan, is very important in this setting. If there is a brain metastasis and one liver metastasis or a second tumor in the lung opposite the main tumor, the brain lesion isn’t “precocious”: it’s now a cancer that has at least a couple of areas of distant spread. This doesn’t mean that the brain metastasis shouldn’t be treated aggressively, but the situation isn’t as favorable as having a stage I or II NSCLC cancer in the chest and a single brain metastasis. For that matter, many people also make the distinction between early stage NSCLC, especially stage I, in the chest and locally advanced NSCLC aside from the brain metastasis. The idea of the precocious metastasis doesn’t apply as well if the staging outside of the brain is IIIB. The most encouraging results have been in the patients with an early stage NSCLC tumor aside from a single brain metastasis. These are patients in whom surgery is often considered both for the lung disease and the brain metastasis. Continue reading
Risk Factors for Development of Brain Metastases
While brain metastases are common, some patients seem to be at higher risk than others. As previously noted, SCLC has a very high risk of spread to the brain. For NSCLC subtypes, several studies have shown that patients with non-squamous lung cancers have a greater tendency to develop brain metastases than those with squamous cancers, which tend toward more local spread. Here is the figure for development of brain metastases in patients treated for stage IIIA NSCLC out of the Harvard/Dana Farber system (abstract here).
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Another trial just published from UCSF evaluating the stage IIIA NSCLC population also found a high risk (55%) of recurrence in the brain after aggressive treatment, and that the risk of brain metastases was higher for patients with adenocarcinoma vs. squamous cell carcinoma (57% vs 34%, a statistically significant difference (abstract here)). The Boston study also demonstrated that patients who had a good response to pre-operative treatment (chemo, radiation, or a combination of both for all but 3 patient who had unsuspected N2 nodal disease at surgery) and cleared their mediastinal nodes at the time of subsequent surgery had significantly lower risk of developing brain metastases than patients who had N2 nodes positive at the time of surgery:
Brain Metastases from Lung Cancer: An Introduction
I’m going to cover the general concepts of management of brain metastases, a subject that is still evolving because of our growing technology, particularly with stereotactic radiosurgery (SRS), commonly referred to as gamma knife. In many cases, our practice has moved a bit ahead of the data. We’ll start with some general issues and then, over several posts, cover issues from surgery to radiation to medical therapy.
Brain metastases are very common, somewhere in the range of 150,000 – 170,000 patients with cancer who develop brain metastases each year in the US, which makes it the most common complication of cancer (abstract here). Lung cancer is the most common underlying cause, accounting for something in the range of half or a bit more of those cases (abstract here). In SCLC, more than 10% of patients have brain metastases at the time of diagnosis, and more than 50% of those patients with SCLC who aren’t treated with prophylactic cranial irradiation (PCI) will develop brain mets later, generally within two years of diagnosis (abstract here). In NSCLC, PCI has also been considered due to the fact that up to up to half of the total number of people with NSCLC develop brain metastases as well at some point; this has become a common “sanctuary site” for disease to recur first or recur only after treatment for stage I – III disease. Continue reading
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