We will be discussing two separate but related articles today.  The first is a detailed assessment of skin cancer risk in CLL patients.  The second is an intriguing paper that links Vitamin A supplementation to reduced risk of aggressive melanoma.  I am sure this is not the last word on the subject and I do not want you to rush out and take massive amounts of Vitamin A without consulting your physicians.  But anything that gives a bit more protection to our guys and reduces the risk of having to fight a two front war with CLL and skin cancer is definitely worth a second look.

Expert Review: Skin Cancer Risk in CLL Patients

In case you were a skeptic, here is a detailed “Best Practices” article from no less than the Mayo Clinic that talks about skin cancer in CLL patients.  There is no doubt our guys are more at risk of skin cancer.  And garden variety squamous cell carcinoma (SCC), basal cell carcinoma (BCC) are more likely to be aggressive in immune compromised patients (read, CLL patients) and therefore require more extensive Moh’s surgery.  The Mayo article goes beyond that and discusses the impact of malignant melanoma (MM) and Merkel Cell Carcinoma (MCC)  (see image alongside) on overall survival in CLL patients.  As you would expect, it is not a good idea to have to fight melanoma or merkel cell carcinoma, while you are also struggling with the “good” CLL cancer.

Merkel Cell Carcinoma

Since Merkel cell carcinoma may be a new one to some of you, it may be worthwhile to get some details about this form of skin cancer.

  • Merkel cell carcinoma is often observed as a fast-growing, painless nodule on your skin. The nodule is often shiny and may be skin colored or shades of red, blue or purple.
  • The majority of Merkel cell carcinomas appear on skin surfaces frequently exposed to UV radiation (sun exposure, tanning beds etc) but they can develop anywhere on your body, even on areas where the sun don’t shine.
  • People with weakened immune systems — such as those with CLL, HIV infection or those taking drugs that suppress the immune system — are at increased risk of Merkel cell carcinoma.
  • Other risk factors are: people with pale skin, older individuals (risk increases after 50, though even younger people can get it), those that have already had basal cell or squamous cell carcinoma.
  • Merkel cell carcinoma has a nasty habit of metastasizing quickly, even while it is under treatment.  often, it travel first to nearby lymph nodes and then may spread to your liver, bone, lungs or brain.
  • Recently, it has been shown that Merkel cell carcinoma may be triggered by a virus, the Merkel cell polyomavirus.  As immune compromised people, CLL patients are more at risk of all sorts of viral infections, including this polyomavirus.  Here is the link to a detailed article discussing MCC and viral connections.

Below is the abstract from Mayo.  If skin cancer is something you worry about (and in my humble opinion every CLL patient should be aware of increased skin cancer risk), the full length article is something you should read and file away for future reference.  Send me a personal email and I will help you locate it.

J Clin Oncol. 2012 Feb 21. [Epub ahead of print]

Chronic Lymphocytic Leukemia Is Associated With Decreased Survival of Patients With Malignant Melanoma and Merkel Cell Carcinoma in a SEER Population-Based Study.

Brewer JD, Shanafelt TD, Otley CC, Roenigk RK, Cerhan JR, Kay NE, Weaver AL, Call TG.

Mayo Clinic, Rochester, MN.

PURPOSE: To delineate outcomes of malignant melanoma (MM) and Merkel cell carcinoma (MCC) in patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin’s lymphoma (NHL).

PATIENTS AND METHODS: We identified patients with MM or MCC reported to the Surveillance, Epidemiology, and End Results program and analyzed the effects of history of CLL/NHL on overall (OS) and cause-specific survival after MM or MCC. Expected survival was derived from patients with MM or MCC without CLL/NHL.

Results: From 1990 to 2006, 212,245 patients with MM and 3,613 patients with MCC were identified, of whom 1,246 with MM and 90 with MCC had a prior diagnosis of CLL/NHL. Patients with MM and a history of CLL/NHL had worse-than-expected OS as measured by standardized mortality ratio (SMR; SMR for CLL, 2.6; 95% CI, 2.3 to 3.0; SMR for NHL, 2.3; 95% CI, 2.1 to 2.6). MM cause-specific survival was worse than expected for patients with a history of CLL (SMR, 2.8; 95% CI, 2.2 to 3.4) or NHL (SMR, 2.1; 95% CI, 1.7 to 2.6). Among patients with MCC, OS was worse than expected for those with a history of CLL (SMR, 3.1; 95% CI, 2.2 to 4.3) or NHL (SMR, 1.9; 95% CI, 1.3 to 2.8). MCC cause-specific survival was worse than expected for patients with a history of CLL (SMR, 3.8; 95% CI, 2.5 to 5.9), but no difference was observed for NHL (SMR, 0.9; 95% CI, 0.4 to 2.1).

CONCLUSION: Patients with CLL before diagnosis of MM or MCC have significantly worse OS and MM or MCC cause-specific survival than those without a history of CLL/NHL.

PMID: 22331952

The bottom line is quite clear.  In this large retrospective study with more than a thousand patients with malignant melanoma and another 90 patients with merkel cell carcinoma – all of whom also had CLL / NHL, patients with CLL diagnosis before diagnosis of MM or MCC had significantly worse overall survival.  And conversely, CLL / NHL patients were more likely to die of these two types of skin cancers than people who did not have CLL / NHL.

The first graph above shows overall survival of CLL and NHL patients from the time of diagnosis of malignant melanoma (MM).  Notice how much steeper the colored lines are (gold for NHL, blue for CLL) when patients had to fight a two front war complicated by melanoma.  The black lines are for reference, where the CLL / NHL patients did not have melanoma.  Likewise, the second graph shows the same information but with reference to merkel cell carcinoma (MCC).  These two skin cancers – MM and MCC – are the two most deadly form of skin cancers and something I would not wish on any of  you.

Below is the take-home quote from the Mayo experts that is worth its weight in gold:

 Our analysis provides strong evidence that patients with a history of CLL or NHL are at a higher risk of death as a result of MM (malignant melanoma) or MCC (merkel cell carcinoma) once one of these cancers develops.  When considered with the higher risk of and more aggressive behavior of other skin cancers (eg, basal cell carcinoma, squamous cell carcinoma) in patients with CLL and NHL, an annual dermatologic skin examination and patient education regarding sun protection and skin self-examination seem appropriate for patients with these lymphoid malignancies.

I have been preaching all these points for about a decade now.  It is good to have this kind of expert guidance clearly spelled out.

Link between Vitamin A and Melanoma risk

Now for the second article I want to discuss today.  It takes a more positive look at melanoma risk, namely at a potential way of reducing the risk.

J Invest Dermatol. 2012 Mar 1. doi: 10.1038/jid.2012.21. [Epub ahead of print]

Association of Vitamin A and Carotenoid Intake with Melanoma Risk in a Large Prospective Cohort.

Asgari MM, Brasky TM, White E

1] Division of Research, Kaiser Permanente Northern California, Oakland, California, USA [2] Department of Dermatology, University of California, San Francisco, San Francisco, California, USA.

Laboratory data suggest that intake of vitamin A and carotenoids may have chemopreventive benefits against melanoma, but epidemiological studies examining the association have yielded conflicting results. We examined whether dietary and supplemental vitamin A and carotenoid intake was associated with melanoma risk among 69,635 men and women who were participants of the VITamins And Lifestyle (VITAL) cohort study in western Washington. After an average of 5.84 years of follow-up, 566 incident melanomas were identified. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of melanoma associated with dietary, supplemental, and total vitamin A and carotenoid intake after adjusting for melanoma risk factors. Baseline use of individual retinol supplements was associated with a significant reduction in melanoma risk (HR: 0.60; 95% CI: 0.41-0.89). High-dose (>1,200 μg per day) supplemental retinol was also associated with reduced melanoma risk (HR: 0.74; 95% CI: 0.55-1.00), as compared with non-users. The reduction in melanoma risk was stronger in sun-exposed anatomic sites. There was no association of melanoma risk with dietary or total intake of vitamin A or carotenoids. Retinol supplementation may have a preventative role in melanoma among women.

PMID: 22377763

While this is an interesting study, I would like to caution you about massive doses of Vitamin A without first checking it out with your physicians.  Vitamin A is a fat soluble vitamin and unlike water soluble vitamins (vitamin C is a good example of a water soluble vitamin), it is not easily excreted from the body along with urine.  In other words, it gradually accumulates in your body, in the fatty tissues.  Too much of anything is not a good thing.

It is also worth noting that the results are not quite crystal clear.  The authors saw a reduction of melanoma risk only with high-dose supplementation with retinol, compared to to those that did not get the retinol.  Women seem to benefit more than men.  The benefit was also more pronounced in those parts of the body that were more sun exposed.  All in all, I found this study raised quite a few more questions than it answered.  For example, if retinol reduced melanoma risk, it is kind of hard to see why a similar relationship was not seen in the case of overall dietary intake of vitamin A.  Perhaps it has to do with the bigger oomph of high dose retinol supplementation.  As always, prudence is the better part of valor.  Send me a personal email if you want my help in locating the full article.

Imiquimod, anyone?

We have several articles on our websites regarding a topical cream called imiquimod (brand name in the USA is “Aldara”).  Imiquimod is thought to work through improving the patient’s own immune system via facilitating the release of several important cytokines.  Initially imiquimod was approved by the FDA for genital warts and actinic kertosis. More recently it has been seen to have benefits in a number of different skin diseases, including SCC, BCC, herpes skin lesions and even malignant melanoma. Here is the link to the article.  You can read it for free by just clicking on the link.  Even if the language is a little dense, there are a whole lot of before-and-after pictures of patients with malignant melanoma treated with topical imiquimod cream – pictures that will knock your socks off. Here is an example.

A, Right lower leg showing multiple papules and an ulcerated nodule of cutaneous melanoma metastases.

B, After 4 months of treatment with 5% imiquimod cream, complete remission with residual hyperpigmentation is seen.

We need your help

In a recent slew of articles we discussed the issue of potential for conflict of interest when important clinical trials are paid-for entirely by pharmaceutical companies that have a lot of money riding on the outcome of the trials.  There is a reason why prestigious professional journals now require authors to disclose their financial or other relationships with drug companies.  There have been enough scandals over the years to satisfy even the most ardent conspiracy buff!

Unfortunately, well conducted and large scale clinical trials cost a lot of money and effort.  Money is always in short supply, that goes without saying.  But increasingly, I am worried that even many of our expert centers and CLL experts are finding it easier to conduct research that is almost entirely paid for by the pharmaceutical industry.  Smaller trials conducted by lesser known institutions without this massive support of  industrial patronage suffer due to lack of funds, lack of visibility and ultimately lack of ability to recruit patients.

Literally a beacon of hope in this grim scenario are the excellent clinical trials conducted at the National Institute of Health (NIH), National Cancer Institute (NCI), National Heart, Lung, Blood Institute (NHLBI).  If you are not familiar with the excellent work done by these tax-payer funded research institutions, please check out the member comments that follow each of the articles where I reviewed clinical trials at the NIH / NHLBI.  Here are the links to the articles for your convenience.  To say these clinical trials and the researchers involved in conducting them get rave reviews would be a huge understatement.

A well designed PCI-32765 clinical trial

A clinical trial perfect for our times

I received a request for getting people to sign a petition authored by Dr. Meltzer of Johns Hopkins, for more robust financial funding for the NIH.  The request is attached below and pretty self-explanatory.  You may have to visit http://www.whitehouse.gov/ and  register to get an active account on the “We the People” website (if you do not already have one) before you can sign the petition.  May I add my voice to that of Dr. Meltzer.  As patients with an incurable cancer, as members of a community that is small potatoes compared to more lucrative “solid” cancers such as breast cancer, prostate cancer etc, we are at a huge disadvantage when it comes to new drug development and trustworthy analysis of clinical trial outcomes that are not at the mercy of commercial interests.  We  need a vibrant and well funded NIH / NCI / NHLBI.  Signing this petition is in our own self-interest.  The deadline is March 18th.  Please sign the petition yourself, and get the word out to your friends and family.

Stephen J. Meltzer, M.D.

The Harry & Betty Myerberg/Thomas R. Hendrix Professor

Departments of Medicine (GI Division) and Oncology

The Johns Hopkins University School of Medicine & Sidney Kimmel Cancer Center

1503 E. Jefferson Street, Room 112

Baltimore, MD 21287

smeltzer@jhmi.edu<mailto:smeltzer@jhmi.edu

I was on a recent conference call with White House officials, during which research funding was discussed. It seemed to me that these officials did not fully understand the central importance of NIH funding to our national research enterprise, to our local economies, to the retention and careers of our most talented and well-educated people, to the survival of our medical educational system, to our rapidly fading worldwide dominance in biomedical research, to job creation and preservation, to national economic viability, and to our national academic infrastructure. In response to a question from a participant, they staunchly defended the proposed flat $30.7 billion FY 2013 NIH budget as being perfectly adequate, remarking that “The NIH receives more funding than any other research entity; it will continue to be strong; it will do just fine.”

This statement is patently false. The proposed flat NIH budget will severely exacerbate a catastrophic crisis that has been ongoing since 2003, when growth in NIH funding fell (and has continued to fall every subsequent year) behind the rate of inflation. As a consequence of this deeply flawed public policy, promising careers have been cut short, amazing research projects have been aborted, hundreds of laboratories nationwide have shrunk or been shut down, established and accomplished senior researchers have been forced to abandon their programs, young scientists have departed from research of even left the country (even after many years of productive training), thousands of ancillary jobs have been lost, our worldwide medical research dominance has been eroded (ceded to China, India, and other nations), and a large support network of laboratory supply and biotechnology companies has been drastically attenuated.

I write to let you know about a recently created petition on “We the People”, a new feature on WhiteHouse.gov  , and ask for your support. If this petition gets 25,000 signatures by March 18, 2012, the White House will review it and respond!

We the People allows anyone to create and sign petitions asking the Obama Administration to take action on a range of issues. If a petition gets enough support, the Obama Administration will issue an official response.

You can view and sign the petition here:

http://wh.gov/81O

Here’s some more information about this petition:

Increase NIH budget to $33 billion dollars next fiscal year! A flat $30.7 billion will kill jobs and hurt research.

Increase NIH spending to $33 billion! The proposed flat NIH budget will close labs nationwide, kill good-paying jobs, damage our worldwide medical research dominance, and hurt state economies. NIH jobs cannot be outsourced. NIH funding created 350,000 jobs and contributed $50 billion to the national economy in 2007! In-source our jobs!!