New Effective Treatment for Opioid-Induced Constipation

   It’s not a glamourous topic, but severe constipation due to opioid (narcotic) medications is a major issue in managing pain from cancer.  Opioid medications like morphine, oxycodone, dilaudid, and fentanyl are often needed to manage cancer-related pain effectively, but they come with some baggage.  Although I strongly encourage my patients who need narcotics to not worry about becoming addicted (you can become dependent, which may be unavoidable with appropriate use but is a physiologic effect, not a desire or need to abuse these agents), but opioid-induced constipation is the most common and challenging side effect we encounter as the downside of achieving good pain control that many cancer patients need.   In fact, there’s an old quote in medicine, “The hand that writes the narcotic prescription is the hand that writes the laxative prescription.”   Not exactly poetry, but I think of it every time I write a prescription for a needed narcotic, and I also write for one or more bowel medications to counter-balance the constipating effects of narcotics.  Otherwise, you’re pretty much asking for trouble.

   Even with many of the agents available, from stool softeners to laxatives to suppositories and enemas and more, some patients who need significant amounts of narcotics can get pretty miserable from constipation, and we find ourselves sometimes wondering how to balance the competing problems of pain and severe constipation.  So when a new and effective treatment for opioid-induced constipation is tested and becomes commercially available, it can represent a major benefit for the people who need it.

   That new agent is called relistor, or methynaltrexone, and unfortunately it is only able to be administered as an injection under the skin, like insulin, but it was the subject of a recent randomized study published in the New England Journal of Medicine that showed the benefit it can offer (abstract here).   This drug blocks a subset of the opioid receptors, called mu receptors, that are along the gut and cause constipation when turned on by opioids, but this drug also can’t get through the blood brain barrier to reverse the pain control effects of opioids.

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New Treatment Being Developed for EGFR Inhibitor Skin Rash

The leading side effect of EGFR inhibitors, both the oral tyrosine kinase inhibitors (such as tarceva (erlotinib)) and the IV monoclonal antibodies (such as erbitux (cetuximab)), is rash, dryness, and other skin side effects. While a rash sounds modest to many people compared to many of the leading problems with chemo, many of the members here can attest that while an EGFR rash can range be as mild as a pimple or two, it can also be itchy, painful, and be as severe as a skin rash covering large amounts of the body, sometimes with open lesions. And for some patients, the skin side effects can require dose reductions or even lead patients to discontinue their EGFR inhibitor, even if it might help against their lung cancer.

As described in a press release last week, Hana Biosciences, based in South San Francisco, has initiated a study of topical menadione, a precursor to forms of vitamin K that also activates EGFR. This topical medication is being studied in the setting of both a prophylactic treatment and as a treatment for skin side effects that emerge on treatment. This research is being led by Dr. Mario Lacouture at Northwestern, who I’d consider to be the leading expert in EGFR rash treatment right now.

There have been several posts and forum threads on managing the rash, but it’s very encouraging to see that not only is more attention being paid to this problem, there are actually trials being run, even with new agents, that are trying to reduce a side effect that can significantly worsen the quality of life for patients on EGFR inhibitors, sometimes even keeping them from getting the drug, or perhaps a dose that could be managed chronically if the rash was controlled more effectively.

EGFR Inhibitor Combination Tested in Advanced NSCLC

As I’ve described in various posts about targeting the epidermal growth factor receptor (EGFR), one of the main signals that is important in many lung cancers, there are agents like gefitinib (iressa) and erlotinib (tarceva) that target the internal switch that triggers activity inside the cell, and there are agents like cetuximab (erbitux) that work on the external front end receptor to block activity:

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I must admit that I’ve always been curious whether combining these two appoaches, giving an oral EGFR tyrosine kinase inhibitor (TKI) with a weekly IV EGFR monoclonal antibody would potentially provide a synergistic inhibition and impressive activity. For the first time, Ramalingam and colleagues have published their limited experience of combining iressa and erbitux in a small trial of patients with advanced NSCLC (abstract here). Unfortunately, the results don’t look particularly impressive.

My friend Dr. Ramalingam has just recently moved from Pittsburgh to head the lung cancer program at Emory University in Atlanta, but while at the University of Pittsburgh he and colleagues there conducted this study to assess the safety and get a sense of the activity of a combination of iressa with erbitux. Iressa, the first EGFR TKI approved for NSCLC, was studied at the previously approved standard dose of 250 mg daily (subsequently found to not be significantly superior to placebo in a large trial of previously treated patients with advanced NSCLC and taken off the market). Erbitux was given at increasing doses, starting at a rather low dose and escalating to a point of maximum safe/tolerable dose for the combination. For these “phase I” trials of safety, small numbers of patients are usually enrolled. This study included 13 patients who had received at least one prior chemo regimen for advanced NSCLC.

Although the numbers were small, there were no responses seen, and only 4 patients (31%) even showed stable disease. Progression was pretty quick, and 3 patients developed severe declines in blood magnesium levels, which is a known side effect of erbitux, but this was a high rate.

The investigators also tried to do some molecular studies from the subset of 10 patients who had some tissue to work with. They didn’t find any EGFR mutations that would be expected to be associated with robust EGFR TKI responses. They also did not detect any RAS mutations that are generally recognized as being very unlikely to show a response on EGFR TKIs.

There are many reasons why this little study is far from the definitive word on the subect. Iressa at the dose tested is not as effective as tarceva, so perhaps the results would have been more favorable with tarceva. Perhaps these results just happen to be particularly disappointing in a small number of patients who happened to not benefit, but a larger study would have shown better results that represent reality better. Or maybe this combination isn’t particularly useful in a general population but could be very impressive in a more selected population, based on EGFR mutations or never-smoker status. I’ve also wondered whether adding erbitux to tarceva in a patient who has now become resistant to tarceva after a prior good response would restore activity. But we don’t have any evidence on any of these questions.

For now, I think all we can say is that a combination of EGFR TKI and monoclonal antibody doesn’t lead to blockbuster activity in NSCLC. But expect to see a lot more trials of targeted agents in coming years.

Large Trials Completed with Zactima (ZD6474, vandetanib) in Advanced NSCLC

We’ve been following the development of a drug called Zactima (also known as ZD6474, or vandetanib) for over a year as it continues to be studied in lung cancer, and the work continues. As first discussed in my initial post on this agent, this agent actually inhibits BOTH VEGF and EGFR (in fact, the name vandetanib comes from VandE, I learned). It’s an oral tyrosine kinase inhibitor of these receptors, but it appears to inhibit VEGF at a lower dose of 100 mg daily than the 300 mg daily that block EGFR in addition to VEGF. Because of that, we presume it behaves differently depending on the dose used.

This may well be significant because the dose that has moved forward is 300 mg as a single agent, based on encouraging work at this dose compared with iressa (gefitinib) (prior post here). In contrast, a different phase II trial tested both the 100 mg and 300 mg doses with taxotere (docetaxel) compared with the same chemo alone (described here; note: this is the same as the initial post on zactima). In that trial, the lower dose appeared to be clearly better than the higher dose. My suspicion has been that this could be because the higher dose is where you block EGFR activity, which I’ve described as being potentially detrimental when giving chemo concurrently, although this remains unclear). On the basis of this early work, trials moved forward with the 300 mg dose as a single agent, and the 100 mg dose in combination with chemo).

There are four main trials evaluating zactima in advanced NSCLC, and three of them have now been completed. The first that accrued all of its intended patients is the ZEST trial that I described previously, back in November of 2007. In this study of patients with advanced NSCLC who had received one or two lines of prior chemotherapy, zactima was compared head to head with tarceva (erlotinib). We haven’t hear any results from that study. The other major single agent trial of zactima is called the ZEPHYR trial (Zactima Efficacy trial for NSCLC Patients with HistorY of EGFR and chemo-Resistance — a rather forced if clever acronym: “nobody leaves this room until we come up with a great name for this trial!”), which is directly comparing zactima to a placebo in patients who have already been on an EGFR inhibitor like tarceva or iressa:

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This trial is still in the process of enrolling a target of 930 patients (more information here)., The sites are outsde of the US, because of the great difficulty in enrolling American patients on placebo-controlled trials.

The news this week (press release here) was that two other large trials with zactima have also been completed. The larger one, called ZODIAC (Zactima in cOmbination with Docetaxel In non-smAll cell lung Cancer), another tortured acronym in the name of cleverness, apparently reached its target of 1380 second line advanced NSCLC who were randomized to receive either taxotere alone or the ame chemo with zactima at 100 mg per day:

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Targeting Insulin-Like Growth Factor 1-Receptor (IGF-1R) in Cancer

In addition to several molecular targets that have been well studied for several years, such as the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), new targets are emerging as potentially fruitful approaches to combating cancer. One of these is the insulin-like growth factor receptor, or IGF-1R.

IGF-1R is involved in the process of transforming a normal cell into a cancer cell when certain cancer trigger genes, called oncogenes, are activated. Activation of this receptor sets off a complex cascade of effects that promotes tumor survival and growth. There have also been studies that have demonstrated elevated blood levels of IGF in patients with several kinds of cancer. Tumors also tend to express high levels of IGF compared with normal tissues. Read the rest of this entry »

Recent Results with Talactoferrin: Reason to Move Forward

As I described in part I of this subject (last post here), lactoferrin is an immunostimulatory protein that is found in highest concentrations in breast milk (hence the name), and the recombinant form talactoferrin alfa (TLF) was combined with chemo in a randomized phase II study of front line advanced NSCLC in which the combination was associated with an impressively higher response rate than chemo alone. The rate of side effects was also significantly lower among the patients who had TLF added instead of a placebo. While these results are promising, the agent made relatively little splash in the lung community, generating little attention from the poster presentation of this work in 2006. But this was just a phase II trial with 110 patients, so it’s reasonable to hope for corroborating evidence of benefit before believing these results are more than a fluke. In 2007, another randomized phase II trial of TLF vs. placebo, now as single agents, was reported that supported the findings from the first line trial, this trial with overall survival as the primary endpoint.

The trial presented last year by Parikh and colleagues from several centers in India enrolled 100 advanced NSCLC patients who had previously received either one line (about 3/4 of patients) or two lines (about 1/4 of patients) of prior systemic therapy, who were randomized to receive oral TLF or placebo (ASCO abstract here, subsequent World Conference on Lung Cancer abstract here). Treatment with this oral agent was twice daily for twelve weeks, followed by two weeks off, for a total “cycle” of a rather unconventional 14 weeks. Repeat CT scans were done about 7 weeks into the treatment, with a total of 81 of the original 100 patients getting that follow-up scan and considered evaluable.

So what happened? As shown in the figure below, overall survival was significantly higher in the recipients of TLF, whether you look at the median survival an “intent to treat (IIT)” analysis of everyone enrolled (whether you received enough treatment to be re-scanned seven weeks later), the 81 patients who were evaluable. In addition to median survival, six month survival was significantly greater for TLF recipients by both an IIT analysis and looking at just the evaluable patients:

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Talactoferrin Alfa (TLF): Mother’s Milk Becomes Cancer Treatment

We’ve covered several novel agents for treating lung cancer, but a new one that has shown promise in early studies and now is the subject of larger phase III trials is a drug called talactoferrin alfa (TLF), from a small company based in Houston called Agennix. I think it’s possible that much of the reason there hasn’t been much buzz behind this treatment, despite the very intriguing results, is that this agent is so different from the mechanisms we know well already, like blocking angiogenesis, inhibiting EGFR, combining these approaches, etc. And the fact that this is a small company far from the big pharma and biotech hubs like New Jersey and the Bay Area probably contribute; in addition, all of the results thus far have been generated out of India, which has many lung cancer patients but few recognized leaders in the field, so there hasn’t been an identifiable spokesperson to introduce the lung cancer world to the novel agent and concept of TLF. But let’s try to remedy this situation, because I’m inclined to keep my eye on it for the next few years.

TLF is an oral protein that is a recombinant product that is structurally identical in all material respects to human lactoferrin, an important immunomodulatory product that is expressed throughout the body in immune cells. As the name implies, it is found in highest concentration in breast milk, and it is important in contributing to the development of an infant’s immune system. The largest component of the immune system is actually the “gut-associated lymphoid tissue” (GALT), where the cells of the immune system interface with vast amounts of new proteins from the outside world (food). TLF is purported to work by getting taken up by the immune cell centers of the gut, called Peyer’s patches, where they induce immature dendritic cells, which are some of the heavy lifters teaching the rest of the immune cells what to focus on and what to ignore, to mature. Although the immune system is very complicated, the end result is that TLF can activate dendritic cells of the immune system and thereby lead to increased immune function against tumor cells.

(Click on image to enlarge) Please don’t worry if you don’t “get” these immune system principle: I show the figure in case people are interested, but it’s not on the quiz. Your immune system is like your television — you don’t need to know how it works to be able to use it. Suffice it to say that there are several lab-based studies with animal models of cancer that support this immunostimulatory role for TLF. But the real issue is what it does in humans. Read the rest of this entry »

Introducing Dr. Leanna Standish, Naturopathic Oncology Expert

I’m very grateful to have assistance from Drs. Labriola and Bufi, who have both provided input and answers to questions over the past year on the broad topics of naturopathic medicine and supplements. As the site transitions from OncTalk to GRACE, we’re also moving from pretty much just me to having more of a plurality. I’ve been glad to have the additional voices (or at least keyboards) of Leah de Roulet and Dr. Laskin join in recently, and now I’d like to also introduce Dr. Leanna Standish. I hope it will be helpful to get additional perspectives on these topics.

Dr. Standish is an expert in naturopathic medicine and is actually board certified in the nascent field of naturopathic oncology. In addition to being a central member of the faculty at Bastyr University, a leading center for naturopathic medicine here in Seattle, and is also on the faculty and conducting research at the University of Washington. Her formal biosketch is below, but expect to see her commenting in the Q&A forum on naturopathic medicine subjects and, I hope, adding some posts as well.
Leanna J. Standish, ND, PhD, Dipl. Acup., FABNO

Dr. Standish is a physician and neuroscientist. She is a naturopathic physician, board certified in naturopathic oncology, who has focused on cancer integrated medicine and research much of her 17 years in medical practice. She is also a licensed acupuncturist. Dr. Standish is on the faculty at both Bastyr University and the University of Washington. She is principal investigator on numerous NIH grants and author of over twenty peer-reviewed publications, several books and textbook chapters. Currently her research projects include medicinal mushrooms as immunomodulatory breast cancer therapy, complementary therapies for hospice and palliative care, and qi gong for the treatment of malignant brain cancer.

Heat Shock Protein Inhibition as an Anti-Cancer Treatment

There’s a new class of anti-cancer drugs that are being studied, including in lung cancer, known as heat shock proteins, or HSPs. These are sometimes referred to as “stress proteins” because they can be induced to be generated in higher concentrations in response to stresses like heat, cold, low oxygen levels, etc. But HSPs are also present in cells in the absence of significant environmental stress, just as a normal component of the cellular contents. They work as a chaperone protein, alongside of other proteins to ensure that those proteins are in the right shape, which is required to have proteins function properly, as well as the right place when needed. In the context of cancer, HSPs can also assist in the cancer-promoting activities of a wide range of several “client” oncogenic (cancer-inducing) proteins. So inhibiting HSPs, such as one designated HSP-90, is a potential novel mechanism for interfering with the activities of these critical proteins and the overall function of cancer cells.

One such agent that is working its way through clinical testing is IPI-504, from Infinity Pharmaceuticals (perhaps a misleadingly large name for a very small company). In the interest of full disclosure, Infinity’s vice president of clinical development and medical affairs at Infinity is David Grayzel, MD, who was a friend in the year below mine in med school and whose brother, Jon, was a good friend in my med school class who attended my wedding (which was an intimate affair with only about 50 people). Despite our connection, David is among the 98% of my old friends who I haven’t kept in touch with, but I do run into him every year or two at the very large annual ASCO (American Society for Clinical Oncology) meeting every spring. But he’s now overseeing the development of several drugs that are working their way into testing, and IPI-504 is their leading candidate and was the subject of a recent press release. We’ll see if he still returns my calls…

The announcement and another precending one note that the recent report of phase I work with IPI-504, an IV agent, was associated with stable disease in 7 of 9 patients at the time of first repeat CT evaluation. In addition, two of four patients who happened to have undergone a PET scan on repeat follow-up had a partial response based on European criteria, although it should be noted that PET scanning to assess response is not a standard practice and isn’t anything close to being as established as a CT scan to assess response.

Interestingly, some preclinical work in cell line suggests that the activating mutations of EGFR depend on the HSP-90 protein for stability and that IPI-504 may (bolded and italicized) be useful in EGFR-resistant populations (abstract here). For instance, the T790M mutation is one that has been found in approximately half of the prior EGFR mutation responders to iressa or tarceva once they show progression on these agents, and preclinical lab work suggests that IPI-504 may reverse that proces. However, that’s not human work. But it does lead us to the hypothesis that this agent may be useful in patients who have become resistant to EGFR tyrosine kinase inhibitors despite a mutation.

The new phase II clinical trial with IPI-504 will enroll 20 patients with advanced NSCLC who previously received an EGFR inhibitor, and this group will be equally divided between those with a known activating EGFR mutation and those with a normal or “wildtype” non-mutated EGFR target (the kind we don’t associate with special sensitivity to drugs like tarceva). If responses are seen using the more typical CT-based response assessment criteria for trials, they’ll plan to enroll 19 additional patients on the cohort(s) in which some convincing evidence of activity is seen. The schedule for treatment will be weekly IV administration for two consecutive weeks, followed by a week off, for each cycle this schedule was tested in another phase I trial). According to the press release, this particular trial is now open at Mount Sinai Comprehensive Cancer Center in Miami Beach, FL, and at Yale Cancer Center in New Haven, CT, with some other sites coming on board (I’ve had some discussions with Dr. Grayzel but don’t think I’ll be participating in this one).

This isn’t the only heat shock protein inhibitor being evaluated, but it may well be one of the first ones for which we get some clinical data in lung cancer. I’ll give updates when new trials are opening up. In the meantime, HSP inhibitors represent an intriguing avenue for targeted therapy in lung cancer that we’ll hear more about in coming years.

Vinflunine (Javlor) as Second Line NSCLC Option?

Although much of our focus has been on targeted therapies, there are still new conventional chemotherapies that are being introduced and may have a meaningful impact on lung cancer. One that has been tested in late clinical trials, including a phase III randomized study, is vinflunine, which is a novel version of a chemo drug called a microtubule inhibitor, in the same general family as navelbine, one of our more commonly used drugs in NSCLC (and broadly useful in many cancer types). Leading side effects have most typically been decreased blood counts, fatigue, and GI problems like nausea/vomiting, abdominal pain, and constipation. Unlike taxol and taxotere, it doesn’t require any steroid premedication and is given by vein over just 10-20 minutes, typically one day every three weeks.

After the earliest studies, vinflunine was developed in lung cancer, including a second-line trial in 60 patients previously treated with platinum-based chemo (abstract here). There was an 8% response rate and another 50% with stable disease, so overall we can say that there’s proof of activity. But the big test was a randomized phase III trial conducted in Europe, randomizing 551 patients who had received first line chemo, to now receive either taxotere IV every three weeks or vinflunine IV every three weeks (abstract here):

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