Fwd: THE MOSS REPORTS Newsletter (04/18/04)

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19 Apr 2004 03:15:16 -0000

" Cancer Decisions "

THE MOSS REPORTS Newsletter (04/18/04)

 

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Ralph W. Moss, Ph.D. Weekly CancerDecisions.com

Newsletter #129 04/18/04

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HERE AT THE MOSS REPORTS

 

 

This week we report on a new treatment for kidney cancer. As always, we have

tried to analyze this finding using the yardstick of " patient benefit. " It may

seem painfully obvious that cancer treatments should benefit those who take

them. Yet all too often treatments are advocated that do something else-such as

temporarily shrinking tumors or, in this case, increasing a period of

progression-free survival without actually prolonging life.

 

At the Moss Reports we try to measure treatments by what they do for patients.

We carefully examine the scientific basis of claims. This is how we look at

complementary and alternative (CAM) as well as conventional approaches. If you

think you could use an objective overview of the treatments for your kind of

cancer please do not hesitate to contact us. We have reports on over 200

different kinds of cancer and try to keep current on a wide variety of

treatments. You can order reports from our website, www.cancerdecisions.com, or

call our office at 800-980-1234 (814-238-3367 from outside the US). We look

forward to helping you.

 

 

ON THE IMMUNE TREATMENT OF KIDNEY CANCER

 

 

In February, Dr. Dieter Jocham and his colleagues in Lubeck, Germany published

an article in the Lancet on a new kidney (renal cell) cancer vaccine. This

" adjuvant autologous vaccine " was shown to slow the progress of renal cell

cancer (RCC) after the surgical removal of the affected kidney (an operation

called radical nephrectomy). The researchers concluded that their vaccine " seems

to be beneficial " and " should be considered " for similar patients (Jocham 2004).

Meanwhile, the Lancet's editorialists hailed this paper as a " milestone " and an

" immunological breakthrough " (Fishman 2004).

 

I certainly have no objection to doctors who use vaccines to treat kidney

cancer. In fact, I think it's a better idea than just waiting for cancer to

recur. But has this vaccine's effectiveness really been proven? How, exactly,

did the researchers measure the success of the therapy?

 

They measured it not by whether or by how much the treatment extended the lives

of the patients but by how long their disease was kept stable before it began

relentlessly progressing again. (This is what is meant by so-called

'progression-free survival'). The authors claimed that they chose

progression-free survival as the primary goal of their treatment " because even

with surgery for metastatic disease and modern immunotherapy …survival for most

patients is between 12 and 18 months, and fewer than 5 percent survive longer

than 5 years. "

 

This struck me as odd. What one really wants out of any therapy is to have one's

life prolonged (with of course a decent quality of life). Yet here is a

treatment being lauded in one of the world's leading medical journals for doing

something very much less than that. Increasing the time before the disease

progresses may or may not be desirable, but it is hardly equivalent to actually

increasing life span.

 

Although life prolongation using immunotherapy has been an elusive goal, how

does that justify lowering the bar in this way and fatalistically substituting

" progression-free survival " for " overall survival " ? As the Lancet editorialists

themselves remarked, " …overall survival is of compelling clinical interest and

is the standard by which other adjuvant approaches were rejected. " So true.

Survival is what matters. Then why didn't the Lancet hold the authors of this

paper to the same standard to which it holds others?

 

Dr. Jocham and his colleagues also state that many patients with metastases from

kidney cancer (RCC) " enter clinical trials with several combinations of

therapeutic approaches, " which have a variable effect on their individual

outcomes. For these reasons, they say, " benefit from an adjuvant treatment

delaying or preventing progression can be anticipated in patients with

renal-cell carcinoma. Therefore, we did not use overall survival as the primary

endpoint. "

 

Once again, this seems to me to be faulty reasoning. One can always evaluate the

overall survival of patients who are treated after surgery and who receive

various kinds of immune treatment; in such a situation vaccination simply

becomes another variable. If the authors' vaccine truly improved overall

survival, this would only strengthen their argument. If it had no such impact

this would put the study's overall significance in doubt. And in the event that

it actually diminished survival (unlikely, but not impossible), then this would

urgently need to be addressed by regulatory authorities. Choosing

progression-free survival as the measure of a treatment's worth is akin to

judging the effectiveness of a diet not by whether the subjects lose weight, and

if so, how much, but instead by whether they fail to gain any more weight for a

limited period of time.

 

To repeat, increasing the progression-free interval is far less important than

increasing overall survival. Besides, an assessment of precisely when, and how

much, progression has occurred is not a simple or straightforward measure.

Overall survival, on the other hand, is eminently easy to measure, and free of

any subjectivity whatever, since a person is either alive or dead.

 

 

Italian Treatment

 

 

It is also far from clear that delaying tumor progression is always desirable,

if by delaying progression one does not also increase survival. As Drs.

Giancarlo Pizza and Caterina de Vinci of Bologna, Italy, have previously shown,

their regimen of vaccines and immune modulators can prolong actual survival in

kidney cancer (RCC) from 2 up to 46 months, even without making tumors shrink

(Pizza 2001). Yet their diligent work has not received the attention that it

deserves.

 

I am aware that the survival data might require years of follow-up to reach

statistical significance. But since, as the Lancet paper stated, the " primary

endpoint of the trial was to reduce the risk of tumour progression…or death, " I

feel it would have been important to include mortality data in the paper.

 

Although I strongly support cancer immunotherapy, particularly for this type of

kidney cancer, I am concerned about raising unfounded hopes. Progression-free

survival is a therapeutic straw man. By adopting this as a therapeutic goal and

aspiring to it, instead of aiming at nothing less than life prolongation,

researchers may give patients an unfounded reassurance that they are on the road

to recovery, when in fact they are not. This could result in profound

psychological distress and lost opportunities for some patients.

 

It is tempting, in the face of repeated difficulties, to substitute surrogate

goals for actual life prolongation. I am hardly alone in questioning the value

of progression-free survival as a meaningful yardstick of the benefit of new

approaches. At a meeting of the Food and Drug Administration's Oncology Drugs

Advisory Committee last year, panelists were asked whether they would accept

progression-free survival as a primary endpoint for new drug approval in

inoperable, locally advanced cancer. The vote was unequivocally against: no-15,

yes-4 (FDA 2003). I would have voted with that majority.

 

(This article was written with the assistance of Drs. Giancarlo Pizza and

Caterina de Vinci of the Immunodiagnosis and Immunotherapy Unit, 1st Division of

Urology, S.Orsola-Malpighi Hospital, Bologna, Italy. Dr. Pizza can be contacted

at gpizza)

 

 

--Ralph W. Moss, PhD

 

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References

 

Center for Drug Evaluation and Research, Food and Drug Administration (FDA).

Oncologic Drugs Advisory Committee, Endpoints in clinical cancer trials and

endpoints in lung cancer clinical trials, December 16, 2003. Retrieved February

26, 2004 from:

http://www.fda.gov/ohrms/dockets/ac/03/transcripts/4009T1.htm

 

Fishman M, Antonia S. Specific antitumour vaccine for renal cancer. Lancet

2004;363:583-84.

 

Jocham D, Richter A, Hoffmann L, et al. Adjuvant autologous renal tumour cell

vaccine and risk of tumour progression in patients with renal-cell carcinoma

after radical nephrectomy: phase III, randomised controlled trial. Lancet

2004;363:594-99.

 

Pizza G, De Vinci C, lo Conte G, et al. Immunotherapy of metastatic kidney

cancer. Int J Cancer 2001; 94: 109-20.

 

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IMPORTANT DISCLAIMER

 

The news and other items in this newsletter are intended for informational

purposes only. Nothing in this newsletter is intended to be a substitute for

professional medical advice.

 

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