Several members have asked about the appropriate dose of avastin (bevacizumab), which is really still a controversial subject.  It’s worth exploring how we got here and where we are now.

   While other doses of avastin have been used with other tumor types, the first study in lung cancer that used avastin tested two different doses, 7.5 mg/kg or 15 mg/kg combined with carboplatin and taxol (paclitaxel).  This work was done at Vanderbilt Univ. Cancer Center by Dr. David Johnson and colleagues, and Dr. Laskin worked with them for a couple of years.  This study had the following design:

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   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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   Dr. Laskin and I have had a bit of a back and forth discussion about the names to use for our treatments in lung cancer.  The preference for our clinical meetings is to use the scientific, generic names for drugs — erlotinib instead of tarceva, pemetrexed instead of alimta, etc.   That convention has evolved because we feel that using the “trade names”, the marketed names that sound zippier, or at least easier to remember (aloxi instead of palonosetron), is too commercial, like doing a little advertising for the company or the drug rather than being more pure and sticking to the science and the scientific names for the drugs.

   When I give a talk to oncologists, I routinely use the scientific names, but sometimes docs will give feedback asking you to use the marketed names because it’s easier to remember which drugs you’re talking about when you don’t use the 4-5 syllable names.  So my approach since I started writing here has been has been to use the trade names, because I presume that most patients and family members find these names much easier to remember and keep track of: hence tarceva instead of erlotinib and sutent instead of sunitinib.

   But Dr. Laskin’s posts had included the generic names of drugs until I changed them based on my own presumptions, and our discussion makes me reflect that we should ask you directly what you would prefer.  Given that about a third of respondents feel that pharmaceutical company support for GRACE could compromise the integrity of the information provided (based on the poll conducted here over the last month), I don’t think I should make decisions for the reading audience.  Let members/viewers decide whether you would prefer the generic names or the marketed names.

   So now there’s a poll: please just mark your preference.  Avastin or bevacizumab?

   One of the issues we struggle the most with, as oncologists, patients, and families, is how to choose a therapy that won’t make someone feel worse. There are so many things to factor into these decisions: what is the baseline function of the person, what comorbidities (other chronic illnesses) might interact or interfere, what side effects are acceptable or worth the risk, to what degree is the cancer interfering with their functioning and can this be reversed with chemo, and of course what does any individual patient want and expect from chemo? Not to mention the choices between a few different agents or combinations of agents!

   The issue of “performance status” (PS) is fundamentally important in lung cancer, especially in non-small cell lung cancer (NSCLC). There are different scales we use to measure this, which have been posted and discussed previously. Most publications use the Eastern Cooperative Oncology Group (ECOG) scale – partly because it’s rated 0 – 4 which is easy to remember. Zero is normal, and 4 is very debilitated, essentially bed-bound. Perhaps it is somewhat surprising that despite all of the fancy molecular markers and blood tests we have, a person’s functional impairment of PS is one of the most important predictors of how “bad” a cancer is. The other two factors are stage (how much cancer is there?) and degree of weight loss.  It is well described, and there are other posts on the site elaborating on this, that if someone is very sick either from the cancer or from other concurrent illnesses, standard chemotherapy will only make things worse.  But there’s an “in between” group, with a performance status of 2, who may not be as well served by the more aggressive standard approaches but still may benefit from cancer treatment.

   The great hope of the next generation of “targeted” therapy is that oncologists will be able to more accurately predict who will benefit from which drug and that the newer drugs will be less toxic and thus perhaps even better for people who are too sick to tolerate our current forms of chemotherapy. (more…)

   A couple of things of note for the OncTalk community:

   First, you may have noticed that Dr. McCune posted an article on survivorship issues.  She’s not an uninvited hacker who’s posting on the site, but a requested additional faculty member who’s going to help run the bigger enterprise over on the GRACE website, where there will be a section devoted to cancer treatments, symptom management (everything from nausea to pain control to bowel care, etc.), and survivorship/long term follow-up issues.  She’s a longtime friend and an oncology pharmacist who is an Assocaite Professor in the Department of Pharmacy at the University of Washington and is the Clinical Director of the Pharmacokinetics Lab at the Seattle Cancer Care Alliance (the clinical hybrid of the University of Washington and the Fred Hutchinson Cancer Research Center).  She received her PharmD at the University of North Carolina, where she was a key member of a multidisciplinary team in thoracic oncology there, so she’s quite well-versed in lung cancer and writes review chapters in pharmacy textbooks on lung cancer management and other topics.  So she’s pretty well qualified to help out here, and as both a friend and a colleague I’m delighted to have her join in.  She’s going to be a great help. 

   Second, although we’re quite close to having the new GRACE website be functional, the web guys over-promised on a launch today (this follows a new tradition of me assuring people the transition is only weeks away since December).  I think it will be very, very soon, but until you’re shuttled over to the new site, which we want to be functional and ready to roll before the move, it’s business as usual here.  So no asking, “Are we there yet?”.  Soon…really soon.

Hello everyone, I wanted to follow-up on Dr. West’s post about cancer survivorship a few days ago.  The term “cancer survivorship” can mean lots of different things to different people.  In this post, cancer survivors are those patients who finished their cancer treatment and are now being followed to see if their cancer returns and if they have any long-term side effects to the cancer treatment. 

One important thing for all cancer survivors is to have a summary of your cancer treatment.  A one page summary about your specific treatments - surgery, radiation, and chemotherapy.  There is no established guidelines for what the summary should state for lung cancer survivors.  This summary will help you as time goes on and you get further away from your cancer treatment.  It will also help other health care professionals taking care of you as it’ll be a quick summary of your treatment.  Another important thing is to get the contact person and number for medical records of where you received your cancer treatment.  That way, if you need to get your medical records, you’ll already know who to talk to. 

In terms of what you can expect, there is very little information about long-term side effects to cancer treatments for lung cancer.  Most of the information about cancer survivorship is obtained from adults who survived highly childhood cancer or from breast cancer survivors.  Especially as we have more lung cancer cancer survivors, it will be really important that we get more information about their health after the treatment to try to keep healthy.  A great example is the “how to quit smoking” post. 

This is my first post, so please tell me if you need more information or explanation.  I look forward to working with you all!

-Dr. McCune

    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. (more…)

   The topic of paraneoplastic syndromes has been on my “to do” list, but it has taken far too long… so let’s get to it.

   Paraneoplastic means alongside cancer, and that’s because they are weird manifestations not of the cancer that are caused directly by the tumor but at distant sites from the cancer, such as by the cancer turning up the production of a protein or peptide (piece of a protein).   They really aren’t being mass-produced as part of the cancer’s needs, but more of a side effect, just copying these genes that happen to be innocent bystanders.  Another potential mechanism of these syndromes is stimulation of an antibody response by the body, and these antibodies against the cancer cross-react against normal body cells, turning the immune system against the body (causing an auto-immune disease).   This is commonly against neurons in the setting of SCLC.   The cells of origin for SCLC are neuroendocrine cells, so deranged cells starting as neuroendocrine can have features that look similar to the immune system to neurons, and the endocrine portion means that these cells have differentiated to have a good ability to package proteins and peptides.  With that background, it shouldn’t be a surprise that SCLC is the most common form of cancer to be associated with paraneoplastic syndromes.  And these can be associated with a HUGE range of symptoms from low serum sodium levels (caused from a syndrome of inappropriate anti-diuretic hormone, or SIADH) to neurological disorders like Lambert-Eaton myasthenic syndrome, and everything in between. (more…)

   The National Lung Cancer Partnership (NLCP) is listed among useful other resources on our website, but they’re actually another nonrofit organization with whom I and OncTalk have had an ongoing cooperative and actually very complementary relationship.  Started by lung cancer expert and true leader Joan Schiller at the UT-Southwestern in Dallas, NLCP started as Women Against Lung Cancer and had a high priority of promoting both the study of lung cancer in women and patient sex differences, and also developing opportunities for female researchers and clinicians in lung cancer.  As it grew, it expanded to include more than sex differences and gained momentum to integrate more men in its mission of research and promotion of the entire field of lung cancer.  It has coninued to grow as a stronge voice in the lung cancer community, and it has increased its partnerships as part of a larger network to strengthen the lung cancer community.  Among these partnerships, they’ve also helped to encourage me and the nascent nonprofit GRACE (athough not with any grant support yet — hint, hint). 

   Patient advocacy is clearly an important part of this community, and the network of complementary organizations advancing the field of lung cancer.  Toward that end, NLCP is running a Lung Cancer Advocacy Summit in Chicago from May 27-29, immediately before the Annual Conference of the American Society of Clinical Oncology (ASCO), the largest cancer meeting of the year.

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   There’s a really helpful resource for patients, developed by several leading experts in EGFR-based therapy and specifically the very common skin toxicity associated with EGFR inhibitors like iressa, tarceva, erbitux, and some others.  I’ve already described some early ideas about rash management (prior post) and a more recent medical education program video on the same subject (prior post here).  This is a summary article (here) published in the free oncology journal The Oncologist, but I think that more important than the brief review article are the summary poster and brochure for patients.  Rather than recapitulate the content myself, I’ll just reproduce them for you to view here (click on any of these images to enlarge). 

   Here’s the poster (also available as a pdf here):

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   During the entire time I’ve been commenting on the most evidence-based and commonly used agents for previously treated patients, I’ve focused on taxotere, alimta, and tarceva (example in prior post here).  In fact, that overlooks an agent that has actually been tested in a large study and been found to have similar activity to taxotere, but it remains pretty much an afterthought.  The drug is topotecan, tested in an oral form that is just becoming commercially available; here I’ll summarize the trial that illustrates that topotecan is a reasonable option but also suggests why it remains relegated to a lower priority than the other three options we tend to think of more readily.

   At the ASCO meeting in 2005, Dr. Rodryg Ramlau from Poland presented the results of a large phase III international trial (ASCO abstract here) that directly compared oral topotecan to the standard of IV taxotere as a second line therapy for advanced NSCLC (subsequent publication abstract here).  This study randomzed 829 previously treated patients enrolled from both Western and Eastern Europe to receive either taxotere at the typical dose of 75 mg/m2 IV one day every three weeks, or the altenative of topotecan by mouth at 2.3 mg/m2 for each of the first 5 days of a three week cycle.  Treatment continued until there was evidence of progression or excessive side effects:

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  Just last week I described in a prior post the news that a large trial of Nexavar (sorafenib) had been reported as negative in first line advanced NSCLC, and with some evidence of an increased risk of death on the novel agent in combination with chemo in the subset of patients with squamous cell NSCLC.  AstraZeneca just put out its own press release that reports (amidst more positive news about trials in colon cancer) that an important NSCLC trial being done in Canada, known as BR.24 and studying an anti-angiogenic pill, has been closed due to toxicity issues. 

   The drug in question is known as AZD2171, or recentin, and it’s an oral inhibitor of the vascular endothelial growth factor (VEGF) receptor.  This receptor is similar to EGFR, and Recentin blocks the tyrosine kinase portion of the receptor on the inside of the cell (making it a tyrosine kinase inhibitor, or TKI), the back end that sets off a cascade of activities that ultimately lead to angiogenesis, or new blood vessel formation that aids in the growth and spread of many cancers. Recentin binds to the VEGF receptor extremely well, so it has the potential to be a remarkably potent antiangiogenic agent. 

   The trial was known as BR.24 (BR for bronchus) and was being conducted by the National Cancer Institute of Canada, and it was designed to test recentin along with chemo, specifically the same combination of carboplatin/taxol that is so commonly used and studied for patients with previously untreated advanced NSCLC.  The trial was designed to directly compare chemo with Recentin to chemo and a placebo, and unlike the experience with avastin, this trial included patients with squamous cancers, treated brain metastases, and patients on therapeutic doses of blood thinners like coumadin.  It was designed to stop after about 100 patients had progressed or died (the randomized phase II trial portion), then look at the data to see i it looked promising enough and safe enough to proceed with a larger enrollment to really test whether recentin adds to chemotherapy (the phase III component of the trial). (more…)