Supportive care
Nausea, bone metastases, anemia and growth factor support
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Low Testosterone with XALKORI (Crizotinib): A Newly Identified Side Effect
It started with a patient reporting an unexpected side effect. A 35 year old ALK-positive man with lung cancer who was on XALKORI (crizotinib) noted that he had markedly diminished libido lower energy that had been worsening while on treatment, despite the fact that his cancer appeared to be responding well His doctor checked his testosterone (T) level and noted it was well below the normal range, then referred him to the endocrinology clinic for consideration of testosterone replacement therapy, which he decided to do, and which helped with his symptoms. Because this occurred at the University of Colorado, where they have more experience with patients on XALKORI than almost any other institution, they checked testosterone levels of as many men as they could find on XALKORI and compared the results to a comparable group of men with lung cancer who were not on XALKORI.
Low T levels lead to fatigue and depression, hot flashes and night sweats, potentially insomnia, as well as diminished sexual interest and function. Low testosterone (sometimes called hypogonadism) is relatively common in cancer patients overall, though it historically hasn’t been well studied. It’s generally unclear whether low T is caused by the underlying disease, the treatment, other medical issues, or some combination of these factors.
The initial observation from the patient at the University of Colorado led to the report that was just published online in the journal Cancer, showing that 100% of their male patients on XALKORI had a T level below normal (range 241-850 ng/dL there, though this varies a bit from lab to lab), compared with just 6 of 19 matched control patients with a similar distribution of age and other factors, median T levels 131 vs. 311 ng/dL. Also very interestingly, a few patients who stopped and started XALKORI due to other side effects and had their T levels checked at a few time points along the way, showing a remarkably good correlation between T levels falling quickly when on XALKORI, rising within days on a break from it, then dropping again when the drug is restarted:
The authors developed a new policy of checking testosterone routinely in their male patients and referring those with low testosterone to their colleagues for consideration of T replacement therapy that could potentially help reverse both sexual side effects and the fatigue and depression. However, since T can also potentially lead to worse problems with urinary function in men with an enlarged prostate and may accelerate prostate cancer in a man who has that, the overall conclusion is that the decision to start T replacement is an individualized one that depends on the degree of symptoms that a patient has and the anticipated risks and benefits of the treatment.
Selective Androgen Receptor Modulator GTx-024: A New Effective Treatment for Cancer Cachexia?
Anorexia-cachexia syndrome (ACS), a negative spiral of diminished appetite and weight loss (lean body mass), is a common problem in many kinds of cancer, where it not only leads to patient weakness and diminished function but is also associated with shorter survival. While it’s possible that the ACS is a late effect that might be an irreversible product of progression of an underlying cancer, it may also be that ACS directly contributes to a patient’s decline by making them unable to tolerate further cancer therapy.
GTx-024, also now known as Ostarine™ or enobosarm, is a selective androgen receptor modulator (SARM), which activates the androgen (male hormone) receptor and leads to the activation of a wide range of genes in the cell, the net result of which being increased muscle mass, increased bone mass, and often an increase in mood, energy level, sense of well being, and libido. Not surprisingly, these are the exact opposite effects we routinely see in men placed on androgen suppression as a common (and effective) treatment for prostate cancer. Risks include increased hair growth/virilization in women, prostate stimulation and hyperplasia (excess growth) in men, elevated red blood cell counts (potentially to levels above normal), decrease in HDL cholesterol (the “good cholesterol” associated with exercise and decreased risk of cardiac events), and potentially abnormalities in liver function tests.
The phase I and II studies in patients with cancer-associated weight loss thus far have pretty consistently shown that treatment with daily oral GTx-024 leads to a modest (typically 1-2 kg) increase in lean body mass after 16 weeks, while recipients of placebo had no change or a trend toward slight further weight loss. The GTx-024 studies also assessed physical function with a stair climb function, assessing both the time required to ascend stairs and “power”. The pattern is the same as with body mass: there is a modest but statistically significant improvement in stair climb function in recipients of GTx-024, but little or no change in recipients of placebo. Here are some figures that represent the results in the subset of patients with NSCLC, for instance:
In addition, improvement in function on the stair climb exercise was also associated with an improvement in quality of life on an “anorexia-cachexia scale” (so the questions were specifically related to eating and weight issues, not more global qualify of life). More importantly, one subset analysis of this work also suggested that a worse survival associated with weight loss could be abrogated with the addition of GTx-024.
The Troubling Symptom of Bronchorrhea in BAC
Warning: this symptom can be a little gross, so the delicate flowers out there should skip this post.
One of the more unusual but quite vexxing symptoms we sometimes see in lung cancer is called bronchorrhea, which is the copious production of watery sputum, specifically at least 100 ml per day. The setting in which it’s most frequently seen is in bronchioloalveolar carcinoma (BAC), and we typically think of it as being a manifestation of the mucinous subtype. In its worst form, patients can drain vast amounts of phegm each day, typically worst in the morning. Patients have told me that they lean their head down off the bed to drain a half a liter or more at a time before starting their day. Though rare, there have been frequently cited cases that have been life-threatening because of severe electrolyte imbalances that develop from losing so much fluid and salt (case report here). Interestingly, there’s a sheep virus that appears clinically remarkably similar to BAC (though there hasn’t been a human form of the virus ever isolated, despite searching), and I’ve seen video footage of researchers demonstrating bronchorrhea by lifting the hind legs of the sheep into the air, putting a beaker under its nose, and letting the watery mucus drain out for several minutes. Sorry, I told you this post has some indelicate moments. I don’t think that video’s on YouTube yet.
Unfortunately, bronchorrhea is a very difficult symptom to treat effectively. Among the things that have been tried and were written up as possibly successful in individual cases have been steroids (abstract here), inhaled indomethicin (a non-steroidal anti-inflammatory drug)(abstract here and here), a drug called octreotide (reference here), radiation therapy to the most “consolidated” area of lung (reference here), and most recently EGFR tyrosine kinase inhibitors like iressa (full text here, another abstract here, and there are several other reports out there).
The ideal situation is to treat the underlying cancer effectively, rather than just the symptom. In that sense, the EGFR inhibitors are pretty unique in being the best treatment if a particular person’s BAC happens to respond. Based on the fairly large phase II studies that have been done with iressa and tarceva in BAC, the response rate with this class of drugs is in the 15-25% range (see prior post for review). So for the patients who respond to an EGFR agent, it’s a potentially dramatically helpful treatment for a long time. For the majority of patients who don’t respond to one of these agents, the others are things that can be tried, but most of what’s been reported is a single case of a treatment that worked, not a trend of multiple cases. In truth, it’s probably never going to possible to run a study and enroll 20 patients to get a particular treatment, because bronchorrhea is an uncommon symptom of an uncommon disease. But these are a few things that people may try, and I’d be very interested if there are people out there who have had success with any of these approaches. Another one I’d be inclined to try, although I’ve never seen mention of it being done before, is inhaled lasix, the effective diuretic, which is an approach I’ve heard of hospice folks using to treat secretions.
In the meantime, bronchorrhea is often unpleasant, sometimes scary, and potentially life-threatening complication that nobody sees enough to become an expert at managing.
Information and a Resource for Managing EGFR-Based Rash
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):
An Example of Successful Patient-Reported Outcomes (PROs): Tarceva’s Effect on Lung Cancer Symptoms
One of the successful examples of incorporating patient-reported outcome (PRO) measures into an important clinical trial was in the NCI-Canada study BR.21 (abstract here). This study assigned patients to either tarceva or placebo in a 2:1 randomization to the active drug:
(Click on image to enlarge)
This study showed a 9% response rate and an improvement in median overall survival of two months with tarceva, which led to it’s US FDA approval and subsequent widespread use. While the fact that there were responses (although only 8%) and a survival benefit is very important, and probably the most important factor to many patients and oncologists, it’s important to ask whether this comes at the cost of significant side effects. Do patients need to trade quality of life for improved survival? A separate report on the BR.21 trial described PROs on this trial (abstract here).
In BR.21, patients were required to complete questionnaires that asked about a wide range of symptoms commonly seen in lung cancer, as well as global quality of life (QoL) and ability to function normally. Several questions focused on measured of cough, pain, and shortness of breath. The questionnaire was completed before starting treatment, every four weeks during treatment, four weeks after the end of treatment, and (for patients who came off of the study for reasons other than progression, such as side effects) every 12 weeks after ending the study, until progression. Completion rates were about 93% at the start, dipping down to the 80% range as the trial continued. Such a decline in returned responses is typical for QoL patient response assessments.
The symptom-based portion of the study assessment focused on pain, shortness of breath (SOB, also known as dyspnea), and cough. Importantly, the key measure was the time before progression of these symptoms rather than whether there was improvement in these symptoms. Why time to symptomatic worsening rathe than improvement in symptoms? Because you can’t have improvement if you don’t have the symptom, but everyone is a candidate for worsening of symptoms.
The results clearly demonstrated that the survival improvement with tarceva was also accompanied by a relative improvement in cancer symptoms. Specifically, while patients tended to have eventual worsening of symptoms at some point (as indicated by the downward slope of the curves below), recipients of tarceva had an average of a 1-2 month delay in their development of worsening of cough (4.9 vs. 3.7 months), SOB (2.9 vs. 4.7 months), and pain (2.8 vs. 1.9 months).
These differences were all statistically significant, and I would argue also clinically significant, even if we wish the results were better still. Continue reading
More Challenges with EGFR Rashes
Rashes from EGFR inhibitors: we like to see them, because we know that many trials have shown that skin toxicity on drugs like tarceva is associated with better survival (see prior post), but the fact is that sometimes a rash is more than an inconvenience and can really make people miserable, or at least pretty unhappy, as described in the comments and questions from a discussion forum thread today. I’ve described some general management principles for rash in another prior post, but in truth, oncologists aren’t well trained in rash management, and we’ve generally had to learn as we go along, because EGFR inhibitors have introduced this as a new problem in oncology. Tarceva is a well established treatment at this point for lung cancer, and while the monoclonal antibody Erbitux has been used primarily in colon cancer and head and neck cancer thus far, a major lung cancer trial with erbitux was also recently reported as positive (post here), so there’s a strong possibility that erbitux, which is also associated with very significant rashes (and better survival correlated with that), will also be used increasingly for lung cancer.
But there may be more to managing these rashes than the basics I described in prior posts. One of the leading experts is Dr. Mario Lacouture, a dermatologist from Northwestern Univ., who has published some proposed guidelines that are an alternative to some of the other approaches I had previously described (paper here, with a rather complex algorithm figure included). This work focuses on early and aggressive use of minocycline (synthetic tetracycline) and elidel cream, a treatment developed and approved for eczema. In truth, I haven’t used this yet, but I’ve heard from some people who have that Elidel and this general approach can be very helpful.
Dr. Lacouture is included in a panel on a CME program that is available on the web, “The Conundrum of Rash in Management of EGFR Inhibitors“, which includes a detailed and somewhat complex medical presentation (the target audience is doctors) but that also includes several accessible take-home points. It’s available through that website as a 70+ minute streaming video program, or a podcast or MP3 audio file, or you just download the transcript. One thing that the program highlights, in addition to the point that “oncologists are bad dermatologists” (sad but true), is that there is also the ongoing question of whether and when to temporarily hold the EGFR inhibitor therapy and then drop to a lower level. In general, while we’d try to manage people on the highest dose feasible, these are treatments that have the potentially to be chronically helpful. Because of that, I do see it as a question of what is the lowest dose needed to get the desired effect. if someone is having trouble managing on 150 mg and has been stable for many months, I think it’s appropriate to test whether they might feel FAR better on 100 mg and have just as stable disease, or an ongoing response. While we’ve seen that patients who develop a severe rash can do particularly well, there’s no evidence I’m aware of that people who lowered the dose subsequently (and felt better) did any worse than those who continued to suffer at the highest dose they could tolerate with difficulty.
Overall, it’s good to see that we’re starting to see more dedicated study of these EGFR-based rashes, and to get more actual results from these experiences. I think we’ll need to continue to balance between aggressively managing side effects and to learn whether we need to dose to the borders of tolerability or whether reducing dose to a more comfortable chronic solution is appropriate.
Acupuncture for Treating Nausea & Vomiting
I reviewed a few general principles of acupuncture in my last post on its use for pain control. In addition, acupuncture has also been studied as a potential treatment modality for other nausea/vomiting, with some evidence to support its use in addition to anti-nausea (also called antiemetic) medications. Current ACCP guidelines (abstract here, again) strongly recommended acupuncture as a treatment for nausea and vomiting associated with chemo if these symptoms are not well controlled or when side effects from other treatments are problematic. The data aren’t overwhelming, but the recommendation is largely based on acupuncture having very minimal potential adverse effects, so even modest/inconsistent benefits would be felt to outweigh the very slight risk.
A study in the setting of breast cancer (abstract here) randomized patients to receive electroacupuncture to a couple of relevant points, minimal needling at non-acupuncture sites (“sham” acupuncture, a form of placebo control), or anti-nausea medications with no attempted acupuncture, real or otherwise. Electroacupuncture reduced total vomiting episodes from 15 to 5 (median), compared to medications alone, while minimal needling produced results between the full treatment and medications alone (median 10 vomiting episodes).
Studies combining acupuncture with newer generation anti-nausea medications like serotonin receptor blockers (current staples like zofran, kytril, and anzamet, all very similar to each other) have been inconclusive. In a study of patients without cancer but with a form of rheumatic disease that required the chemo medication methotrexate), the combination of acupuncture at the PC6 acupuncture point above the wrist and zofran worked better than zofran alone (full text here). On the other hand, another study that compared zofran and acupuncture at the PC6 point to zofran with sham acupuncture (without penetrating skin) showed no real contribution from acupuncture (abstract here). Other studies demonstrate that acupuncture can reduce nausea/vomiting associated with recent surgery (abstract here) motion sickness (abstract here), and pregnancy (abstract here).
There was a recent meta-analysis of over 1200 patients from 11 trials of various modalities that included acupuncture, acupressure, electroacupuncture, and non-invasive electrostimulation of overlying skin (abstract here). Although not especially dramatic, all of these modalities except non-invasive electrostimulation was associated with some improvement in acute, but not delayed, vomiting.
Overall, the benefits of acupuncture have been rather subtle, but it appears to be an approach that may provide some modest added benefit over medications alone. One interpretation of the negative results in the setting of a bone marrow transplant is that acupuncture may be helpful for more moderate nausea/vomiting challenges, but it may not be effective enough in the setting of very severe anticipated nausea/vomiting. Regardless, these results were enough to have the ACCP say that acupuncture merits consideration as a treatment strategy for nausea/vomiting.
Acupuncture: Introduction and Use for Pain Control
Acupuncture is a complementary approach that originated from traditional Chinese medicine, from a theory that the flow of vital energy, or “Qi” (pronounced CHEE, I believe, unless someone who speaks Chinese tells me otherwise) can be regulated by stimulation of key body areas with needles, heat, or pressure. It is generally felt to be quite safe when performed by properly qualified individuals, although caution is appropriate for patients with a tendency toward increased bleeding or known low platelets. Acupuncture has been the subject of a reasonable amount of study, and it appears that there are significant physiologic effects of acupuncture, mediated through effects on the nervous system. Specifically, studies show effects in terms of changes during acupuncture in release of proteins in the brain, called neurotransmitters, as well as neuro-imaging like functional MRI. While it has historically been utilized for a very wide range of medical problems, the value of acupuncture in evidence-based medicine appears to be considerably more limited, but definitely relevant for a few common issues facing patients with cancer. Continue reading
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