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May 2009

Late health effects of toxicity
of the conventional treatments for Hodgkin's

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

No one disputes the fact that conventional chemo/radiation treatments for cancer in general - and for Hodgkin's lymphoma in particular - are highly cytotoxic. They have to be, in order to kill cancer cells. But healthy cells are not spared either - they do suffer serious damage. So the question whether conventional treatment for Hodgkin's has serious side effects is rather formal. Most of us are familiar with its immediate adverse health effects. The real question is does it cause serious long-term adverse effects in children subjected to it?

The immediate side effects of chemotherapy and/or radiation are well known. Common side effects are hair loss, weight loss, nausea, vomiting, diarrhea, anemia, suppressed immunity, overall sickening and weakness. The body is, in effect, poisoned. Among the possible serious acute side effects are infections due to suppressed immune system, liver and kidney damage, abnormal blood clotting and allergic reactions. 

Common psychological effects are loss of self esteem, lethargy, withdrawal and depression. The conventional treatment for Hodgkin's is invasive and denigrating; it adds to the child's burden of having potentially deadly disease, and is very likely to test protective impulse of its parents, desperate to see it doing better, not worse.

Now, if this was the only price to pay for Daniel's full recovery, it would be well worth it. The problem is that poisoning the body - and especially still developing body of a child - inevitably and significantly increases the risk of

developing serious health problems in the future.

These side effects of chemo and radiation can surface as far as two or three decades - or more - after the treatment. They include secondary malignancies - which, in addition to recurrent Hodgkin's, include breast cancer, lung cancer, leukemia, sarcomas of the bone and soft tissue, non-Hodgkin lymphoma, gastric cancer, melanoma and thyroid cancer - reproductive problems (infertility), cognitive impairment and organ dysfunction - thyroid, cardiac, pulmonary, musculoskeletal, as well as premature death.

While there is no overall statistical data for side-effect-specific rates of incidence, such data has been collected in some studies. It should be fair indicator of the risks associated with the conventional Hodgkin's treatment.

For instance, among 694 children and teenagers at Stanford (Wolden et al, 1998) that have been followed for 1 to 31 years after treatment (13.1 year average), more than half of premature deaths were due to recurrent Hodgkin lymphoma and about 1/5 due to other secondary malignancies. Risk of developing cancer was

10.6 times higher for males, and 15.4 times for females,

with breast cancer and sarcoma being the most common cancer types.

The rates of long-term increase in risk of developing cancer for children treated with conventional chemo/radiation Hodgkin's protocols are staggering. Table below shows data from the Late Effect Study Group (Bhatia et al, 2003), which followed 1380 children 16 years of age and younger (median age at the time of diagnosis 11.7 years) treated for Hodgkin's disease in the 1955-80 period, with 17 years average follow-up period.

POST-TREATMENT CANCER INCIDENCE IN PEDIATRIC HODGKIN'S PATIENTS
Late Effects Study Group (update), Bhatia et al. 2003

MALIGNANCY

INCIDENCE
(% total)

RISK INCREASE

20-YEAR
INCIDENCE (%)

30-YEAR
INCIDENCE (%)

All cancers

143 (10.4)

18.5

10.6

26.3

Leukemia

27 (2)

174.8

2.1

2.1

Non-Hodgkin's
lymphoma

7 (0.5)

11.7

1.5

1.5

Solid tumors

109 (7.9)

18.5

7.3

23.5

Breast (female)

39 (2.8)

55.5

5.6

16.9

Thyroid

19 (1.4)

36.4

1.9

4.4

Bone

8 (0.6)

37.1

0.5

0.8

Colorectal

8 (0.6)

36.4

0.4

2.4

Gastric

3 (0.2)

63.9

0.3

0.6

Lung

4 (0.3)

27.3

0.1

2.1

Risk ratio to expected (general population based) incidence was 79 times higher for any leukemia, and 321 for AML (acute myeloid leukemia) and MDS (myelodysplastic syndrome, blood disorder that can escalate to leukemia) combined. Cumulative 20- and 30-year incidence indicate that some form of post-treatment cancer, like leukemia and lymphomas, are mainly limited to the first 15-20 years following the treatment. Most other cancer forms

keep plaguing patient population at an increasing rate as far as
30 years after treatment, and beyond.

Premature deaths from cardiac diseases resulting from cardiac toxicity of the therapy are the next most frequent "other cause" of premature death in pediatric Hodgkin's patients. Cardiac diseases include pericarditis, valvular defects and coronary artery disease. Conventional Hodgkin's treatment's cardiotoxicity has been associated with chemotherapy agents vinca alkaloids, alkylating agents and anthracyclines (especially doxorubiein), as well as radiotherapy - mantle field radiation, and high-dose mediastinal (mid-chest) radiation.

So, what does the big picture look like, with these major risks combined? You are not likely to get straight answer to that question, if you ask those who should know it and fully inform you. Government sources, like the National Cancer Institute, do mention side effects, but rarely specify the risks. Instead, they use general terms like "increased risk of" or, occasionally, "significantly increased risk".

How much of a risk that implies? My guess is as good as yours.

What you can hear from a doctor are also generalized phrases, like "it depends", "the success - some even use word 'cure' - rate is 80-90%", "it is highly curable malignancy" (with conventional treatment), "serious side effects are rare, and significantly reduced with newer therapies", or alike.

The reality of it - as you already suspect - is not nearly as rosy. After all, these treatments soak the body with toxins and/or radiation strong enough to kill cancer cells. And we all know how tough cookies they are. While Daniel may have had 85-90% chance of being alive in 5 years, the chances that he'll be also doing well after treatment are considerably lower. And the more we go beyond 10-year period,

the more side effects of poisoning the body start surfacing.

They can be very serious and, not seldom, they do cause premature death.

But if you want to know more specifically to what extent,

you have to do your own homework.

Part of the problem in obtaining straight, complete information on post-treatment mortality and morbidity in children conventionally treated for Hodgkin's is that results vary from one Hodgkin's study to another, sometimes significantly. Due to different patient populations (i.e. proportion of favorable vs. unfavorable cases), criteria, procedures and designs, studies most often are not directly comparable.

A quick digression to explain terms "favorable" and "unfavorable": Favorable prognosis in Hodgkin lymphoma is limited to IA, IIA stages, where A stands for "asymptomatic". Unfavorable is for any stage III and IV (metastatic), and for stages I and II with B, E or X annotation, where B stands for the defined set of symptoms (i.e. symptomatic disease), E for extension to a single adjacent extralymphatic organ, and X for bulky disease.

Also, unfavorable prognostic factors are erythrocyte sedimentation rate ESR≥40mm, hemoglobin level Hb<11g/dL, total leukocyte count TLC>13,500, male sex and less than 70% response to the first two chemo cycles (criteria for hemoglobin level and ESR vary somewhat).

Also, the overall efficacy and safety of conventional Hodgkin's therapy has improved, particularly with respect to the period preceding 1960s, and somewhat less from the 1980s on, so that older or mixed data is not representative of the current efficacy/safety level. But plenty of data is available, and it can certainly can be used to create a big picture of the overall efficacy and safety of the conventional - should we say, "law enforced" - Hodgkin's treatment. So let's do it.

In order to keep it simple, only the two most important outcomes are addressed: (1) overall survival rate, and (2) quality of life.

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