Secondary Cancers

veteransOver the years I have lost many members / friends to secondary cancers. Several were killed by aggressive melanoma that rapidly became the hot button issue. One of our Board members with very indolent Bucket A variety CLL died of short fuse lung cancer. Another is dealing with ductal carcinoma of the breast. I even know one brave lady who has more than half dozen different secondary cancers, on top of the original CLL.

But poignant as they are, anecdotal stories like these do not make for robust statistics. Yes, our guys are more likely to develop secondary cancers, either because their genetics makes them more cancer prone to begin with (which may be why they got CLL in the first place), or the existence of CLL makes their wimpy immune systems less than capable of fighting off secondary cancers. Or the chemotherapy drugs they must use precipitates a secondary cancer.  But from a patient’s perspective, the why and how is not as important as figuring out whether secondary cancers decrease our survival chances, whether they impact length and quality of life.

What is the Biggest Killer of CLL Patients?

It is my understanding that majority of CLL patients die as a result of uncontrolled infection, usually some sort of pulmonary infection. So, you can understand the title of the article below was like a kick in the gut. Second cancers are the most common cause of death in this large group of CLL patients?  Dr. Clive Zent of Mayo Clinic is someone I respect a great deal. He is one of the authors of this article and therefore I read the article carefully. The abstract is given below. Send me a personal email if you want me to help you locate this article.

Leuk Lymphoma. 2004 Mar;45(3):507-13.

Veterans with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have a markedly increased rate of second malignancy, which is the most common cause of death.

Kyasa MJ, Hazlett L, Parrish RS, Schichman SA, Zent CS.

Division of Hematology/Oncology, Department of Medicine, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.


Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have an increased incidence of high-grade lymphoid malignancy. The risk of non-lymphoid second malignancy in this population is not well-defined to date. To test the hypothesis that patients with CLL/SLL have an increased risk of second malignancy, we studied the rate of second malignancy in 132 CLL/SLL patients and compared it to the rate of malignancy (excluding non-melanomatous skin cancer) in the Central Arkansas Veterans Healthcare System population of approximately 38,000 veterans over a period of 11.5 years. The rate of second malignancy, diagnosed concomitantly or after CLL/SLL, and the age-adjusted rate of malignancy calculated from tumor registry reports and demographic data, were used to calculate a Standardized Morbidity Ratio (SMR) with 95% confidence interval (CI). Twenty-one (16%) of the CLL/SLL patients had second malignancies (19 non-lymphoid, 1 Richter’s transformation and 1 Hodgkin’s disease), which were fatal in 15 (71%) patients. The SMR for the CLL/SLL population was 2.97 (95% CI 1.84-4.55) for second malignancy and 2.69 (95% CI 1.62-4.21) for non-lymphoid second malignancy. This study of a well-defined CLL/SLL population shows a significantly increased risk of second malignancy, which was the primary cause of death for 9% of all CLL/SLL patients (34% of all patient deaths).

PMID: 15160912

Long term studies spanning a decade or more are very difficult to do. Patients move away, stop responding to questionnaires, get lost in the shuffle of life. Compared to most solid cancers CLL is slow paced, which means meaningful results can be obtained only in specific situations where the patient group is kind of locked in place and the researchers can therefore monitor them over many years.

This study was conducted over a period of 11.5 years, from 1 January 1990 to June 2001, using patients seen at the Arkansas Veteran Health Facility. As you can imagine, because of the nature of VA medical benefits, patients can be followed for many years without too many of them drifting away. Vets may also be more civic minded and willing to obey doctors’ orders to fill out questionnaires etc – I am guessing.

132 patients with CLL/SLL were compared to other veteran patients at the facility who did not have CLL. They looked for all incidences of second cancers, diagnosed at the same time or after CLL diagnosis. Cancers prior to diagnosis of CLL were not counted. Non-melanoma skin cancer (i.e., garden variety basal cell carcinoma and squamous cell carcinoma) were also not included in this study.

This patient group was not exactly representative of the general population. For example, all patients were male (duh, this is a veterans group, before women were routinely inducted into the armed services). They were a slightly older group, median age of 70 years (range 44 – 85 years) and many more of them were smokers than general population at that time period. Most of them lived in a geographically localized, largely rural (agricultural? farm chemicals?) area.

  • 26 (20%) of the 132 CLL patients developed second cancers. There were a total of 29 secondary cancers since some of the patients were “doubly blessed” with more than one secondary cancer.
  • The risk of developing a second cancer increased over time: 25% at the 6 year after CLL diagnosis, 38% at 9 year mark.
  •  Fifteen patients (71%) with second malignancy died during the study period and the most common cause of death (12 of the 15 deaths, a whopping 80%) were caused by their second malignancy.
  • Here is a scary statistic: The median survival of patients with second malignancy was 9.9 months, counting from the time of diagnosis of the second cancer.
  • Second malignancy was the most common cause of death in all CLL/SLL patients (34%) followed by progressive CLL/SLL (18%) and infection (16%).

The authors speculate about the reason why CLL patients were so much more likely (roughly three times more likely!!) to get secondary cancers than the general run of the mill veteran used as the control arm of their study. Possible explanations for the increased risk of second malignancies in CLL/SLL include clonal evolution, genetic predisposition, carcinogen exposure, acquired immune deficiency (HIV, AIDS), and the effects of treatment.

Some Questions Rising Out of This Study

OK, I can buy that long list of possible causes of secondary cancers. This was a meticulously conducted study, patients were carefully monitored and the data mined with a fine tooth comb for possible nuggets of information. But some questions remain in my head.

For starters, the authors point out that the incidence of CLL itself was higher in this veteran population than the general public. Whoa. Why is that? What sets these veterans apart from the general public? Could it have anything to do with their increased exposure to carcinogens? Yeah, these guys lived hard and smoked a lot. I don’t think there are too many people who argue any more about the link between smoking and cancers. Is that the reason why they saw an increased incidence of CLL in their group?

Or is there another carcinogen that these guys had been exposed to in the seventies, something called “Agent Orange”? Most of us who grew up during the Vietnam War era are familiar with this devastating chemical defoliant that was rained down on the forests of Vietnam. Only recently did the VA administration acknowledge possible link between Agent Orange exposure and CLL. As a patient advocate I was jubilant when the hard work of patient groups paid off and Veterans with CLL got full disability coverage for it, if they can show they had been exposed to Agent Orange.  Please read this earlier article on our CLL Topics website if you want to learn more about it.

I wonder if any one has studied rural Vietnamese of that era, to see if there was a huge spike in CLL in that population as well. They surely were “exposed” to a lot more Agent Orange, by the bucket full.  By the way, I am by no means convinced Agent Orange is the only carcinogen used in warfare. It is the only one I am aware of, for that time period.

OK, perhaps the higher incidence of carcinogen exposure (smoking and work-place related carcinogens) might be the reason for higher incidence of CLL in this veterans group. Could it also be responsible for many more secondary cancers as well as more aggressive secondary cancers? I have no way of sorting that out from the data presented in this study. If (and I am walking way out on to the plank here, people) the secondary cancers were also influenced by chemical exposure in this veterans group, then I can understand why secondary cancers were the single biggest cause of death. Not infection, not aggressive CLL, majority of these patients died of secondary cancers. And that, I think, is not the pattern seen in the general population of CLL patients. Something else seems to be going on here – but I could be wrong.

More studies are needed to sort out all this stuff. And it will take time, effort, good researchers willing to do the hard work, altruistic patients who are willing to stick with the program and provide information when asked to do so. But two take-home messages are obvious even from this study. Secondary cancers are scary stuff; anything you can do to avoid them is a very good idea. What are the usual culprits that might increase your risk of secondary cancers?

  • Smoking
  • Obesity
  • Excessive UV exposure
  • Poor diet with insufficient amount of fiber, micro nutrients not present in junk food
  • Uncontrolled and chronic inflammation, which includes gingivitis and tooth decay
  • Uncontrolled viral infections such as HPV infection we discussed in the previous article. HIV infected patients are at much higher risk of secondary cancers.
  • Open sores that are breeding grounds for all sorts of secondary infections

These are all things you can do something about. None of them should come as a surprise to you, experts have been telling us about these risk factors for years now.

There are other risks that are not so much within your control. Baked in the CLL cake is the risk of hypogammaglobulinemia (reduced levels of immunoglobulins), increased risk of autoimmune disease, and dependence on chemotherapy drugs that can play havoc with your already messed up immune system.

Luck plays a big role on how much these risks factor in your individual case. In the final analysis, all you can do is to do the best you can do. After that, call it karma, call it fate, call it roll of the dice, what you will. My husband died because the roll of the dice did not work in his favor. It gives me some small comfort that we played the hand he was dealt to the best of our ability. No regrets on that front.

Roll of the dice