DO INFECTIONS & DECISIONS WORSEN LIFE WITH CANCER?
Do infectious agents cause cancer? Do treatments make us more susceptible to worsened experiences? Let’s assume both propositions hold true. Then you should sit on a mountain top until lightning strikes, ignoring the world and all prospect of an involved life until the tablets of eternity arrive. No, there is a flaw in the model somewhere. We belong in the real world. Our very essence is about living – and we have to do that now! Rather than decry the faults of medical cures, we really should think long and hard about the true objective of cure itself. Perhaps the use of a theoretical definition in this matter is actually setting back our chances for achievement: Or, at very least, putting the task definition a little aside from its correct place. I just heard Lance Armstrong complaining that everyone who thinks of him as a cyclist believes these recent years have been used “sitting on my Ass drinking Beer”. Clear definition is critical. And I think we should take a deep breath, look at some viewpoints from a different perspective, and see whether we aren’t losing chances to help a sizable number of people – by research and by providing information with a sharper focus on the risks for exacerbating our malaise by inopportune treatment, ongoing management and personal lifestyle decisions.
1. TRANSFORMATION OF DISEASE AFTER CLADRIBINE TREATMENT
Here is an interesting article from long enough ago that it escapes referencing by current researchers. It was published almost a full decade past.
Ruben Niesvizky et al, “Epstein-Barr Virus-Associated Lymphoma after Treatment of Macroglobulinemia with Cladribine,” New England Journal of Medicine, 1 July 1999; 341:55.
An extract reads:
A 69-year-old woman received the diagnosis of Waldenström’s macroglobulinemia with IgM kappa in 1991. Because of the progression of the disease, treatment with standard doses of cladribine was initiated in June 1994 and repeated in August 1994. The patient had a remarkable response, with alleviation of her symptoms and more than 90 percent reduction of the serum paraprotein level. Five months after the completion of treatment with cladribine, pain developed in the right hip, and a right acetabular lytic lesion was found. Laboratory tests showed lymphopenia, normal serum viscosity, and a stable IgM level. Additional studies revealed a mass in the liver. Biopsies from both the right acetabulum and the liver revealed morphologically identical lymphocytic infiltrates that were consistent with the presence of diffuse large-cell lymphoma. The patient subsequently died, and an autopsy revealed diffuse large cell lymphoma that was positive for EBV latent membrane protein 1 in both liver and kidney specimens. An antemortem serologic test was positive for EBV.
The crucial statement in this paper, it seems to me, is not that the patient was positive for EBV, but rather that “Cladribine can cause profound immunosuppression, lymphopenia and increased susceptibility to opportunistic infections”. More importantly, the “Epstein-Barr virus (EBV)-associated diffuse large-cell lymphoma developed after treatment with cladribine”.
We have discussed something similar in very recent times…the recent publication from Dana Faber “Increased Incidence of Transformation and Myelodysplasia/Acute Leukemia in Patients With Waldenstrom Macroglobulinemia Treated With Nucleoside Analogs”, which is available at http://www.wmprogram.com/_documents/Publication/Publication129.pdf. There are other retrospective studies of indolent lymphomas that conclude against murine analogues. The Dana Faber discussion notes a report from MD Anderson Cancer Center that indicates EBV was unlikely to be involved in cases there in which LPL/WM transformed to a more aggressive form. [Pei Lin et al, "Diffuse Large B-Cell Lymphoma Occurring in Patients With Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia" Am J Clin Pathol 2003;120:246-253] Hence, the current proposition is that the nucleoside analogues are the root problem. Actually, Niesvizky and colleagues did not say anything different in their antique work. They pointed to a condition that developed after treatment with Cladribine. As necessitated by evidenced-based investigation, these authors quoted an even earlier discussion – nay, a review article:
2. INFECTIOUS & IMMUNOSUPPRESSIVE EFFECTS OF THERAPY
This ancient review is revived at http://jco.ascopubs.org/cgi/content/abstract/13/9/2431 and goes into substantial detail about the “Infectious and Immunosuppressive Complications of Purine Analog Therapy.” Written by Bruce Cheson; J Clin Oncol 13:2431-2448, 1995, it considers fludarabine, cladribine and pentostatin in the treatment of indolent lymphoid malignancies. It reviews the pattern, severity and consequences of immunosuppression and myelotoxicity associated with these agents, as known in published literature at that time when we were all younger.
Each of these drugs induces profound lymphocytopenia. A marked decrease in CD4 cells may persist for several years, while other mononuclear-cell populations recover more rapidly. The spectrum of infections encountered in these patients appears to be altered to include a wide range of opportunistic organisms. Factors that increase the risk of these infections include concurrent corticosteroids, extensive prior therapy, particularly with another purine analog, and poor response to purine analog treatment.
Because of the frequency of life-threatening infections with unusual pathogens that may occur in patients treated with purine analogs, aggressive and early diagnostic evaluation and appropriate use of myeloid growth factors may be necessary to ensure appropriate antimicrobial therapy.
Note that the decrease in CD4 cells for example, might persist for several years. Therefore, steps taken to compensate clinically for the immunosuppressive effects may need ongoing therapeutic management of patients. Surely we have to ask whether that remains an option open to patients in retrospect. Or are we content to haul back in dismay and point to the wonders potentially available in the new world?
3. INFECTIOUS AGENTS AS CAUSES OF LYMPHOMA
Another contemporary approach, it seems, is to look in detail for the insurgencies that make you susceptible to Non-Hodgkin Lymphoma – that can come along and cause infections that subsequently become cause of NHL. An abstracted article from the National Cancer Institute, NIH is the following:
Eric A. Engels “Infectious Agents as Causes of Non-Hodgkin Lymphoma” Cancer Epidemiol Biomarkers Prev 2007;16(3):401-4.
Among exposures presently viewed as possible etiologic factors in non-Hodgkin lymphoma (NHL), infections are close to being regarded as established causes. Infectious agents causing NHL can be classified, according to mechanism, into three broad groups. First, some viruses can directly transform lymphocytes. Lymphocyte-transforming viruses include Epstein Barr virus (linked to Burkitt’s lymphoma, NHLs in immunosuppressed individuals, and extranodal natural killer/T-cell NHL), human herpesvirus 8 (primary effusion lymphoma), and human T lymphotropic virus type I (adult T-cell leukemia/lymphoma). Second, human immunodeficiency virus is unique in causing profound depletion of CD4+ T lymphocytes, leading to acquired immunodeficiency syndrome and an associated high risk for some NHL subtypes. Third, recent evidence suggests that some infections increase NHL risk through chronic immune stimulation. These infections include hepatitis C virus as well as certain bacteria that cause chronic site-specific inflammation and seem to increase risk for localized mucosa-associated lymphoid tissue NHLs. Establishing that an infectious agent causes NHL depends on showing that the agent is present in persons with NHL as well as laboratory experiments elucidating the mechanisms involved. Only epidemiologic studies can provide evidence that infection is actually a risk factor by showing that infection is more frequent in NHL cases than in controls. Given the range of mechanisms by which infections could plausibly cause NHL and our growing molecular understanding of this malignancy, this field of research deserves continued attention.
But this seems to be suggesting a biosphere form of isolation against all possible things we might contact, just in case we contact them. Since that clearly isn’t possible, we each face the reality that after diagnosis our primary problems are to get healthy as best we can and to live well for as long as we can. It will do no good to run around squashing all mosquitoes that have candy cane legs. One of them might have bitten you, of course. But it could have been the goo of the one you squashed those years ago that made you ill. Your real object is to embrace all forms of help that will provide good health for a future of happiness.
4. WHAT DO YOU WANT, CURE OR GOOD HEALTH?
So almost fifteen years after Cheson’s insight was available, when we understood the need to manage opportune infection after treatment…what now? Indeed, shouldn’t we pose the question more broadly? Given what we know, should we just run along happily throughout the years after diagnosis, leaving ourselves open to attack by candy cane legged mosquitoes. Or shouldn’t some energy be spent in quantifying the opportunity for preventative measures that might dissolve those candy cane legs?
Sure, such effort would not be curing LPL/WM – or would it, in fact? If the malady of indolent lymphoma were equivalent to life and not perceived as immediately terminal, then shouldn’t we place priority on getting the best mileage of good health?
The potential adverse effects of treatment need to be highlighted. There can be no dispute about that. But it may not be the most beneficial route to encourage research that continues emitting comparisons concerned with treatment – regarding that as a likely non-recoverable experience -with all focus for the future centered on the incestuous lives of little WM cells. Practical effort at finding ways to estimate the quality of immune surveillance and decrease susceptibility to territorial invaders with candy cane legs seems not to have been high on the agenda. What do you all think – shouldn’t we favor research that takes more than an oblique look at the added exposures coming after treatments which deliver a route of initial escape?
Be well, be wise
IWMF-TALK 17 January 2009