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Institute of Medicine Report Urges Major Policy Change on Tobacco
This week, the Institute of Medicine, a branch of the US National Academy of Sciences, released a 400-page comprehensive report (prepublication available here; 8 page summary brief available as pdf file here). It notes that the rates of adult smoking has dropped by more than 50% since 1965 and that the rates of high school students starting smoking are at all-time lows, but also that these trends appear to be flattening and that tobacco still accounts for an estimated >400,000 deaths each year in the US. The report calls for several significant changes, suggesting that state and local governments should ban smoking in malls, restaurants, and essentially nearly all public indoor spaces, and that the US FDA should regulate the marketing, packaging, and sale of tobacco products. This report also recommends an increase in federal taxes on cigarettes and a plan to gradually reduce the concentration of nicotine in cigarettes to a point below which they are no longer predictive. Some other highlights of the report recommendations include:
banning internet- and phone-based sales of tobacco products
requiring licensing of retail outlets that sell tobacco products
adding graphic picture warnings on cigarette packs, as is done in Canada now
restricting advertising to black and while only, text-based displays, and prohibiting tobacco companies from using terms like “light” and “mild” in their marketing
mandating all public and private health insurers to make smoking cessation programs a lifetime benefit
in addition to substantially raising federal taxes on tobacco products, raising taxes in states with lower tobacco tax rates in order to reduce the practice of inter-state smuggling
dedicating increased funds to tobacco control efforts
The goal of these efforts, according to Mr. Richard Bonnie, who is a law professor at the University of Virginia (who’d have suspected a Virginian would lead this campaign?) would be “reducing tobacco use so substantially that it no longer has a significant impact on public heath”. A lofty goal, and one we’d all love to see. Let’s hope at least some of these ideas get enough traction to move forward.
EGFR inhibitors (Tarceva, Iressa) and Stomach Acid
Several members have raised questions in the last several weeks around the question of whether antacids like garden variety Rolaids or Tums, a class of drugs called histamine H2 blockers like zantac and tagamet, and also proton pump inhibitors (PPIs) like prilosec (the “magic purple pill”), protonix, nexium, etc. that effectively shut down stomach acid may actually be problematic if taken in combination with Iressa or Tarceva (I’m going to focus primarily on Tarceva here, since that’s the drug marketed in the US right now). This issue isn’t one that has been highlighted in the general research and teaching about these oral agents. We do know that absorption is variable, but the reason it is recommended that they be taken on an empty stomach is that it’s more predictable in that setting. Taking these agents with food tends to increase absorption, but unpredictably, so the best way to have a good idea of what’s going into the body is to take the recommended amount (or a dose reduction, as needed) on an empty stomach.
It’s certainly understandable that the absorption from the stomach and gastrointestinal tract be moderated in part by stomach acid or lack thereof, since it’s the job of stomach acid to help digest food (it’s not just to cause heartburn), but there has never been any instruction on having antacids and/or PPIs be considered contra-indicated medicines (advised to not be taken at the same time). In fact, the Iressa package insert does mention that zantac and sodium bocarbonate (antacids), given to keep the pH above 5 (outside of the highly acidic range, which is the low numbers like 1-2), reduce Iressa absorption by 44% in one of the studies by the manufacturer (AstraZeneca). Member NeilB was kind enough to e-mail me this link to a chart in a summary article about the EGFR inhibitors, which notes some of the key drug interactions observed with EGFR tyrosine kinase inhibitors like Iressa and Tarceva. Another official document summarizing extensive pharmacologic information on Tarceva tablets (here) also documents that tarceva absorption appears to be diminished in the absence of an acidic stomach environment and suggests that “caution should be exercised when these medicinal products are prescribed with erlotinib” (Tarceva) (page 19 of this pdf document). Continue reading
Survival and Quality of Life (QoL) in Advanced Lung Cancer: A Devil’s Bargain?
A member recently asked me whether treatment in the second-line or later setting for advanced lung cancer would potentially improve survival at a cost of quality of life, or whether patients can benefit not only in terms of how long they live but also how they live during that time. Since advanced lung cancer, both NSCLC and SCLC, aren’t generally able to be approached with curative intent, it’s important for the treatment not to be worse than the disease. Ideally, patients will even feel better with treatment, rather than have to choose between quality of life (QoL) and quantity of life. However, it’s important to note that the oncology community has not focused on QoL measures nearly as much as survival measures. Partly, this has been because measuring QoL requires expensive and time consuming surveys and/or other measures, and they have not been perceived as enough of a key to FDA approval, patient focus, or physician interest. So here’s a few leads. Continue reading
The Variability of Bronchioloalveolar Carcinoma (BAC): Non-Mucinous and Mucinous BAC
One of the themes that we’ve covered in some of the posts introducing the clinical entity of BAC is the variability in its natural history. In fact, much of what we’ve been learning about BAC has been in the last several years, and we’re still learning more about it all the time. One of the things we’ve struggled with is the range of outcomes, that some patients can experience rapid deterioration and no response at all to EGFR inhibitors, while other patients can have a remarkably slow progression, and they sometimes will have an astounding regression of disease from EGFR inhibitors. It sometimes seems as if there are at least a couple of diseases being labelled as BAC. In fact, that’s the case, and it’s been part of the confusion in why some people don’t fit a simplified view of what is supposed to happen in BAC. So let’s talk about mucinous and non-mucinous BAC.
Non-mucinous BAC is the largest group, accounting for about 40-60% of the patients, while perhaps 30-40% have mucinous BAC, and about 10-15% fall in between and are classified as mixed or indeterminate. In truth, this is pretty high-level classification that is not always (or even often) mentioned in pathology reports of BAC, and I would consider it relatively unreliable if read from a small amount of tissue and/or read by a pathologist without much expertise in lung cancer. In truth, even expert pathologists differ in how they interpret BAC diagnoses. Here’s a slide of BAC and adeno subtypes under the microscope:
(click to enlarge)
Mucinous BAC is the subtype that is associated with a cough productive of thick sputum, and it tends to appear more localized and pneumonia-like on CT scans than non-mucinous BAC, which appears most commonly as a buckshot appearance of lots of tiny, diffuse nodules:
EGFR Inhibitors in Women and Men
Throughout their development over the past years, the EGFR tyrosine kinase inhibitors Iressa (gefitinib) and Tarceva (erlotinib) have been identified as seeming to be particularly helpful in women compared with men. Only Tarceva is commercially available in the US, but Iressa is widely used in other parts of the world, including Asia, where it continues to be avidly used and studied. Both of these drugs have a consistently higher response rate in women, which has led to some different use patterns in women and men. In fact, some US oncologists relegating Tarceva now just to women, despite the fact that it was shown to have a survival benefit in the general population (of women and men). So what’s the fuss about EGFR-based therapies and women?
The differences in response rate were noted in the first reasonably large trials of EGFR inhibitors, which gave Iressa at varying doses to patients predominantly outside of the US (including significant numbers of patients from Asia) in one trial (IDEAL-1 abstract here), and another predominantly from within the US (IDEAL-2 abstract here). In an analysis of multiple variables in these trials, women had a higher response rate in both; the IDEAL-1 trial reported that women were 2.65 times as likely to respond to Iressa as men were, while the IDEAL-2 trial reported that women had a response rate of 19%, compared with 3% for the men on that trial (an approximately 6-fold difference!! Eighteen of their 22 responses on the trial were in women, even though women accounted for less than half of the patients). As described in a prior post, the larger Iressa trial known as ISEL (abstract here), with nearly 1700 previously treated patients randomized 2 to 1 to receive Iressa or placebo, showed no overall survival benefit; women on this trial had a nearly three-fold higher response rate of 14.7%, compared with just 5.1% for men. In the study of Iressa in patients with advanced bronchioloalveolar carcinoma (BAC) that I led (abstract here), women had a median survival more than twice that of men (19 vs. 8 months), and the response rate was nearly twice as high in women as in men, although this was not statistically significant (20% vs 11%):
(click to enlarge) Continue reading
Better Results from Chemo in Women than in Men
While we are still working on figuring out the mechanisms underlying differences in the lung cancers of women vs. men, the efficacy and survival paint a consistent picture that women with lung cancer live longer than men regardless of the lung cancer subtype, stage, or treatment used (summary here). Large studies have reported that women have an approximately 15-20% improvement in survival, controlling for other variables, when compared to men. Women appear to have a superior survival in surgical trials (abstract here) and also trials with chemo and radiation (abstract here). Although there are some trials in which significant differences are not seen, we don’t see trials in which do better than women with lung cancer.
Turning to sex differences in response to chemo, you can see from a few trials that women typically have a median survival that is 1-2, and in some studies 3-4 months, better than their male counterparts:
(click to enlarge) Continue reading
Sex Differences in Lung Cancer Risk and Outcome
We have rarely divided cancers along the lines of sex, except for the obvious ones like breast, prostate, testicular, ovarian, etc., but there is growing evidence to begin to consider patient sex in the field of lung cancer. (As a semantic point for the delicate souls out there who will wonder why I use the word “sex” throughout this post (but notice my restraint in not putting it in bold), it isn’t an attempt to broaden interest by turning OncTalk into an adults only website: the term gender applies to whether a person identifies themselves as male or female as a sociological variable, but patient sex is the biological, genetic and non-transferable assignment). We’ll start to explore some of what we’re learning, and I understand that some very intriguing information on sex-based differences will be presented at the American Society for Clinical Oncology Annual Conference in early June. I’ll give you those updates when they’re publicly available.
First, there’s the issue of the changing patterns of lung cancer. A review of a large database of cancer patients (free full article here) revealed that younger patients with lung cancer (<50) are more likely to be women, and that women disproportionately develop adenocarcinomas and small cell lung cancer, with a relative dearth of squamous cell carcinomas. This suggests that there are differences in the risk factors that can lead to lung cancer in men vs. women. In addition, I’ve described in a previous post some work by Dr. Heather Wakelee at Stanford that shows a disproportionate number of women who are life-long never-smokers in multiple case series. Continue reading
EGFR Inhibitors for Brain Metastases
Inhibitors of the epidermal growth factor receptor (EGFR), such as Iressa (gefitinib) and Tarceva (erlotinib) are generally known for being often minimally toxic, oral, targeted therapies that can occasionally produce dramatic and long-lasting responses in a minority of patients and more modest, minor responses or prolonged disease stabilization in a larger proportion of patients. They are not widely considered as a treatment for brain metastases, but there are many reports that describe responses, including prolonged ones, of brain metastases to Iressa or Tarceva.
One of the earlier reports (abstract here) came from an Italian friend of mine from the global lung cancer community, Dr. Federico Cappuzzo, who described four patients who received Iressa alone, two having had prior whole brain radiation therapy (WBRT) and had partial responses in the brain, with one lasting up to 15 months, and another ongoing at 11+ months at the time of publication. All of these patients also experienced improvement in their neurologic symptoms. Since then, multiple case reports and small series have described responses of brain lesions in one or a couple of patients who received Iressa or Tarceva, including some patients heavily pretreated with chemo and brain radiation. However, these don’t give a sense of how commonly those responses occur among patients who receive EGFR inhibitors. Continue reading
Smokers and Tarceva: Is More Better?
As I’ve described in a prior post, one of the most consistent findings in the work with the EGFR inhibitors Iressa (gefitinib) and Tarceva (erlotinib) is that never-smokers are far more likely to demonstrate a response and survival benefit than patients who do smoke or did smoke. Here, for instance, is the set of survival curves separated by smoking status for the large randomized trial of tarceva vs. placebo in previously treated patients with advanced NSCLC (abstract here):
(click to enlarge)
We really haven’t explored why that as, and that’s partly because there is a lot we don’t know. We do know that never-smokers are far more likely to have mutations than current or ex-smokers with lung cancer, but it’s really not all or nothing. The likelihood of having an EGFR mutation is higher in ex-smokers than in current smokers, and it’s also a gradually higher likelihood with a longer period since patients quit smoking, and with less overall tobacco exposure in terms of pack-years, the product of the number of packs smoked per day (PPD) x the number of years smoked, so 2 PPD x 20 years would be a 40 pack-year history. You can see that between never-smokers and major smokers are a population of patients who fall in between in terms of their smoke exposure and likelihood of having an EGFR mutation (abstract here):
But it’s probably not all about EGFR mutations, which are still only seen in a minority of patients with lung cancer, somewhere in the 5-15% range in the US (more in Asia). It’s quite possible that one of the more important issues may be the metabolism and different pharmacokinetics (the way a drug is processed by the body, specifically the changing levels in the blood over time) between smokers and non-smokers, which may mean that what is an optimally effective dose in a smoker may be higher than the optimal dose in a non-smoker. Continue reading
Chemo or Chemoradiation as Optimal Induction Therapy for Resectable Stage III NSCLC
One of the more common approaches to treating stage IIIA NSCLC with N2 lymph nodes (mediastinal, or mid-chest, on the same side as the primary tumor) is chemotherapy or chemoradiation before surgery. For those who recommend induction therapy (treatment before planned resection), there is a pretty even split between those who recommend chemotherapy alone and those who recommend chemo with concurrent radiation. So how do knowledgeable people come to different conclusions, and who is right?
Pursuing at least chemotherapy before surgery, rather than just surgery alone, for stage IIIA N2 NSCLC, has been pretty well established for more than a decade. In 1994, two small trials were reported that had randomized patients to either surgery alone or chemotherapy before surgery. One study, conducted by Rafael Rosell and the Spanish Lung Cancer Group (abstract here), stopping after a preliminary analysis with the first 60 patients showed a dramatic benefit in favor of the recipients of chemotherapy. While limited because of the small size, a second trial done in the US by Jack Roth and colleagues from MD Anderson Cancer Center (abstract here) also randomized patients to up front surgery or chemo followed by surgery, and this study also was stopped after 60 patients were enrolled after 60 patients were enrolled because of very significant benefits in favor of the patients who received chemo before surgery. This trial was published just months after the Spanish trial, and alhough there were issues with some of the specifics of the trials, and they only enrolled 120 patients between them, the benefits were so striking that it made pre-operative therapy with chemotherapy a standard approach. The results of these trials are summarized in the following slide/figure:
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