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BLOG: June 2009

Long-term mortality and morbidity after
conventional treatments for pediatric Hodgkin's

Daniel's case - True chances - Late effects - Mortality
Real picture - Hodgkin's kids - Alternatives

   Specific information on long-term morbidity and mortality of highly toxic conventional treatments for Hodgkin's lymphoma is - for some reason - hard to come by where it should be given to you: doctor's office, hospitals, and governmental health organizations. Is there something to hide here? Read on, and decide for yourself.

It has to come as a surprise that there is no complete, reliable database on longer-term mortality related to the standard therapies for pediatric Hodgkin's. The National Cancer Institute (NCI) still sticks to its figure of 91% 5-year survival rate based on data from 1985-94 period, for "children under 20 years of age". Granted, it may not have much of a reason to hurry with the update, since that rate ticked up only four percentage points vs. 1975-84 period.

Media - and medical journal articles - often report that the "success rate" of conventional cytotoxic treatments for Hodgkin's has "dramatically" improved in the last 3-4 decades, making it reliable, near bullet-proof cure. Excuse me? Someone's got something backwards here. What is dramatic about the whole thing is that they - pharmaceutical industry and medical establishment - in the very beginning, decided to use a highly toxic treatment, because they didn't know better. It is dramatic - often tragic - that they were literally learning - and still do - on children what is too toxic to be used. No one sane would call this highly toxic treatment,

with devastating immediate and long-term health effects,

a "cure". It is simple the lesser of two evils, becoming somewhat less bad measured by the frequency of often horrible side-effects it inflicts to children (and adults). Please,

do not glorify it as near-ultimate in medicine and healing.

We have already mentioned that Daniel's statistical chances of being alive in 5 years with this treatment are probably within 85-90% range.

But this statistics is for

voluntary treatment.

Being forced to it against his and his parent's will certainly doesn't make his survival chances better - to the contrary. Without guessing how detrimental it will be in Daniel's case, let's just conclude that Daniel and his parents are forced to a therapy that gives him less than 1 in 8 chance - possibly significantly less - of being alive in 5 years.

That still should be better than no treatment, no?

What are his chances without treatment? The data is scarce, and dated. Some 90 years ago, there is a report that untreated Hodgkin's patients lived 18 months on average (Ewing, Neoplastic diseases, 1920). Some 70 years ago, Craft recorded that about 6% of untreated Hodgkin's cases lived 5 years after diagnosis (Results with Roentgen Ray Therapy in Hodgkin’s Disease, 1940). In 1956, Yue et al study describes a man that lived 11 years without treatment after being diagnosed with Hodgkin's (Miliary Tuberculosis and Hodgkin's Disease), and may have died at least in part as a result of his tuberculosis treatment.

This indicates that the chances of surviving 5 years or more without treatment, after being diagnosed with Hodgkin's are likely less than one tenth of those with the voluntary conventional treatment.


no one is advocating "no treatment" option.

All that has been learned about human health in general, and malignancies in particular, since those days gives also realistic expectations that, if patient would be actively pursuing an alternative treatment under professional guidance, his chances to be alive in 5 years would be significantly better than in those days. They could be comparable to that with the conventional treatment, perhaps even better?

How do we ever get to know if we don't give it a fair try?

Surviving the first 5 years is, of course, very important, but two unavoidable questions are: (1) what are child's survival prospects after that and (2) how the treatment affects its quality of life?

There is no specific official data on these two aspect of the standard Hodgkin's treatments. One would expect that the government should at least obtain - and present - that

crucial information about a treatment

before stepping in to enforce it by law. Well, it did not. For some reason, the research on long term mortality and quality of life after the standard Hodgkin's treatment is limited in general, and particularly scarce when it comes to children. But there is enough data from studies to date to put together a big picture.

Turns out, it is becoming worse as we go further beyond that first 5-year post-treatment period. For research data, we have to depend on a decade old study at the St. Jude Children's Research Hospital (Hudson et al, Increased Mortality After Successful Treatment for Hodgkin's Disease, Journal of Clinical Oncology 1998). Through four subsequent clinical trials, the study followed a total of 387 children and adolescents treated for Hodgkin's at St. Jude from 1968 to 1990. As of April 1997, with the median follow up period of 15.1 years, 316 were still alive.

Most of the 71 who died died from Hodgkin's (36), followed by second malignancy (14), infections (7), heart disease (6), accidents (6), suicide (1) and asphyxiation (1). The risk of developing potentially deadly disease was 12 times higher than in the general population for that age group for second malignancies, 81 times for acute myeloid leukemia, 11 times for solid tumors, 33 times for breast cancer. The risk of dying from cardiac disease was 22 times higher, and 18 times higher for dying from infection.

Most children (66%) were treated by combined chemo/radiation, and the rest either by radiation (30%) or chemo (4%) alone.

In order to broaden this single-study picture, we'll take a look at two other late-effect studies that also include adults. One is a 2003 Dutch study on 1261 patients treated for Hodgkin's before age 41 (26% under age 20, median age at the start of treatment 26 years) between 1965 and 1988 (Aleman et al, Long-Term Cause-Specific Mortality of Patients Treated for Hodgkin’s Disease), and the other is 1997 Stanford University study on 2498 patients treated between 1965 and 1995 (R.T. Hope, Hodgkin's disease: Complications of therapy and excess mortality), which doesn't supply age data.

 Graphs below summarize the results of these two studies.

Despite inevitable differences, there are striking similarities in the big picture between these two studies. In both the rate of dying from Hodgkin's lymphoma is by far the dominant cause of death in approximately first 5 years after treatment, after which it declines and nearly flattens after the 10-year mark. On the other hand, deaths due to other causes are only a fraction of all deaths within the first few years, but keep mounting at an accelerated rate as far as 30 years after treatment.

In fact, 30 years after treatment,

nearly 2/3 of all patients are dead

in the Dutch study: about 24% from Hodgkin's, and nearly 40% from other causes (over 20% from other malignancies, nearly 10% from cardiovascular diseases). The study reports 22% of the patients still alive after 25 years, with the median survival estimated at 28.7 years.

The Stanford study gives nearly identical prognosis: only about 30% of patients is expected to be alive at the 30-year mark.

Comparing St. Jude's children study with these two, the most significant difference is in the total mortality rate at 15 years after treatment. In the St. Jude's study it is roughly one half of the averaged mortality rate in the Dutch - still quite young with 26 years of age average at the time of treatment - and Stanford studies.

There is no factual basis for long-term mortality rate in children treated for Hodgkin's to be so much lower than for the general population. It is known that children are, in general, more vulnerable to late effects of treatment toxicity (in the Dutch study,

the risk of dying from solid tumors, leukemia or heart disease
was the highest for those below 20 years of age

at the start of treatment). Comparing St. Jude's data with those of the Late Effects Study Group, we see that their respective rates of incidence for mortality from secondary malignancy are 3.6% (15.1-year follow up) and 10.4% (17-year follow up). While it can be expected that the latter study has higher incidence, due to its period partly extending into pre-60s, when more intense, single modality treatments were used, the ratio of nearly 3 to 1 is unrealistically high.

There are also other studies that include adults coming up with significantly higher mortality rate than the above mentioned Dutch and Stanford studies. For instance, in a Spanish study on 477 patients treated for Hodgkin's from 1967 to 1993, the overall survival rate at 15 years after diagnosis was only 64%, with nearly equal proportion of favorable and unfavorable cases (Provencio et al, Comparison of the long-term mortality in Hodgkin's disease patients with that of the general population, 1999).

Going back to the Dutch study, it had as high as 50% rate of salvage chemo treatments (additional treatment after the initial one fails). This indicates that the initial treatment may have been made deliberately less intensive - to minimize toxicity - failing to either initiate response, or to produce remission. As a result, many more salvage treatments were necessary, possibly making the therapy more, not less toxic, and long-term prospects significantly less favorable.

On the other hand, in the St. Jude's children study, there was only 67 remissions (17%), but those that have not responded, or have only partly responded to treatments, were removed from the study. That is hardly justifiable, since all the cases should be counted. If child dies at any time after diagnosis because therapy didn't work for it, that should certainly be included in numbers indicating treatment efficacy and risks. Limiting the study to children having complete or near-complete response to the treatment had obviously produced

unrealisticaly high rate of treatment's efficacy/safety.

"Technicalities" like these, that vary from one study to another, are also part of the reason why their results differ, not seldom significantly. But the information they supply is sufficient to get the idea about the range of long-term mortality for children conventionally treated for Hodgkin's disease.

The low point for 20-year mortality is 22% (St. Jude), and the high point - omitting the Spanish study - is 52% (Netherlands Cancer Institute). Since information available suggests that the former is more optimistic, and the latter more pessimistic than what underlying fundamentals suggest, our rough approximation lends at their combined average, 36% or, rounded off, 1/3. In other words,

one out of three children treated for Hodgkin's
with conventional therapy is likely to be dead
20 years after their treatment.

But it gets worse for Daniel. One reason is that his IIB Hodgkin's stage is unfavorable prognostic factor for the conventional treatment. The other is that the trauma of deeply disturbing confrontation with authorities, of being forced to therapy against his and his parents' will - on top of being traumatized by serious illness - can have devastating consequences. No one knows how much it will lessen his chances to be still alive 20 years from now - he would be only 33 at that time - but they may not be better than 1 in 2 - maybe not even that much.

And it is not only about survival. It matters very much to him and his parents - and it should matter to everyone else - how good a life Daniel will have. All of the facts that we have suggest that

he is not likely to have good life after conventional treatment
for Hodgkin's.

The above mortality data suggests very clearly that serious chronic conditions are likely to be a part of child's life long after its conventional treatment for Hodgkin's is over.

Again, there is no specific official data on the overall morbidity resulting from conventional treatment for Hodgkin's, as well as for conventional cancer treatments in general. But a few studies examining post-treatment morbidity for conventional cancer treatments (chemo/radiation) are fairly consistent in their results.

According to the largest of these studies, on 10,397 survivors of childhood cancer treated with chemo and/or radiation between 1970 and 1986, about 2 in 3 report at least one chronic health condition, 1 in 3 report a serious or life-threatening disease - four times higher incidence than in the general population - and 1 in 3 report multiple health conditions (Oeffinger et al, Prevalence and severity of chronic diseases in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study, 2005).

The study has found that those treated for Hodgkin's or brain tumor are at highest risk from developing serious chronic diseases down the road. This indicates that among children conventionally treated for Hodgkin's

MORE than 2 in 3 suffer from chronic health condition,
MORE than 1 in 3 have serious or life-threatening disease, and MORE than 1 in 3 have multiple health conditions

by the time they averaged 26.6 years of age, or so (the figure is for the entire study population).

Evidently, in addition to their life expectancy being severely reduced, all but very few of the children subjected to the conventional Hodgkin's treatments are bound to develop chronic diseases, including those life-threatening, as a result of their "cure".

With these specific mortality and morbidity figures, the conventional treatment for Hodgkin's is beginning to look as much less of a "success" than in its typical official and media presentations.

Let's take another look at it.