Breast Cancer ChoicesTM
|Scrutinizing the evidence for breast
cancer procedures and treatments
|Treatment FAQ Articles Part 2
|Lancet 2001 Jul 28;358(9278):277-286
Polychemotherapy for early breast cancer: an overview of the randomised
clinical trials with quality-adjusted survival analysis.
Cole BF, Gelber RD, Gelber S, Coates AS, Goldhirsch A.
Dartmouth College Medical School, Lebanon, NH, USA. firstname.lastname@example.org
BACKGROUND: Overview analysis involving 18000 women with breast cancer in 47
randomised trials showed that prolonged chemotherapy significantly reduces the risk of
relapse and death compared with no chemotherapy. Here we express the size of the benefit in
terms of quality-adjusted survival time gained. METHODS: We used the Q-TWiST method
(Quality-adjusted Time Without Symptoms of disease and Toxicity of treatment) to provide
treatment comparisons within 10 years' follow-up, incorporating differences in quality of life
associated with times patients spend with chemotherapy toxic effects, after relapse, and
without symptoms of relapse or toxicity. FINDINGS: Within 10 years' follow-up the benefit
of increased relapse-free and overall survival for younger women (<50 years old) who
received polychemotherapy balanced the burdens in terms of acute toxic side-effects,
especially among women enrolled in trials that did not include tamoxifen. Overall,
chemotherapy-treated younger women gained an average of 10.3 months of relapse-free
survival and 5.4 months of overall survival within 10 years (p<0.0001 for both) compared
with the no-chemotherapy group. Polychemotherapy provided more quality-adjusted time
than control across nearly all values of utility weights for time spent undergoing
chemotherapy and time after relapse. The range of benefit was from -0.6 to 10.3 months. For
older women (50-69 years) overall, polychemotherapy also provided significant benefit
compared with no chemotherapy but, compared with younger women, the size of benefit was
less and the range of utility-weight values favouring polychemotherapy was smaller. Average
gains for older women treated with polychemotherapy (with or without tamoxifen) were 6.8
months of relapse-free survival (p<0.0001) and 2.9 months of overall survival (p=0.0001)
within 10 years. The range of quality-adjusted benefit was -3.1 to 6.8 months. For older
women with oestrogen-receptor-poor tumours who did not receive tamoxifen (9% of the
total), the benefit of polychemotherapy was significant and similar to that observed for
younger women. INTERPRETATION: The benefits of adjuvant chemotherapy within 10
years outweigh the burdens especially for younger women (<50 years old) and among older
women (50-69 years) to a lesser degree. Additional studies to compare the quality-adjusted
survival of chemotherapy plus endocrine therapy versus endocrine therapy alone are required
for younger patients with tumours that express steroid-hormone receptors.
Cancer J Sci Am 1995 Jul;1(2):114
Adjuvant Chemotherapy for Premenopausal Breast Cancer: A Meta-
Analysis Using Quality-Adjusted Survival
Gelber RD, Cole BF, Goldhirsch A, Bonadonna G, Howell A, McArdle CS, Mouridsen
HT, Rubens RD, Welvaart K.
Division of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts
PURPOSE: Adjuvant chemotherapy for early breast cancer has been shown to offer an
improvement in recurrence-free and overall survival, especially for younger women, but the
acute toxic effects of this treatment discourage some physicians from prescribing it. The
purpose of this analysis was to determine whether the benefit of 6 months of adjuvant CMF
(cyclophosphamide, methotrexate, fluorouracil) treatment outweighs its costs in terms of
toxic effects. METHODS: A meta-analysis of quality-adjusted survival was performed based
on data from 1229 patients, aged 49 years or younger, randomized in eight trials comparing
CMF versus no adjuvant systemic therapy. The eight trials were included in the worldwide
overview conducted by the Early Breast Cancer Trialists' Collaborative Group. The Q-
TWiST method was used in a meta-analysis that provided treatment comparisons
incorporating differences in quality of life associated with the amount of time patients spend
with subjective toxic effects, after relapse, and without symptoms of relapse. RESULTS:
Within 6 years of follow-up evaluation for patients with node-positive disease, the benefit in
terms of increased relapse-free and overall survival balanced the costs in terms of acute toxic
side effects. This was true even for the extreme case in which a zero value was assigned to all
6 months during which patients might receive adjuvant CMF chemotherapy. Within 10 years
of follow-up evaluation, treated patients gained an average of 1.5 years of relapse-free
survival time, almost 1 year of overall survival time, and 1 year of time without symptoms
and toxicity. CONCLUSIONS: Adjuvant chemotherapy for younger women with node-
positive breast cancer provided substantial amounts of quality-adjusted survival time, even
after accounting for costs associated with toxic effects of the treatment. The Q-TWiST
method represents a valuable tool for comparing treatments because it incorporates patients'
perceptions of their quality of life for therapeutic decision-making.
The title of the article is "Useless Poisonous Cures" (Giftkur ohne Nutzen). Unfortunately, Der Spiegel's
website provides no English translation of the article. I have therefore summarized the contents for
The article reads as follows:
Increasingly sophisticated and expensive cellular poisons are being given to seriously ill patients with
colon, breast, lung and prostate cancer. Now an epidemiologist has analyzed the actual rate of life
extension in such patients. His findings are that despite all the alleged progress, patients do not actually
live a day longer.
On Christmas eve, Erike Meyer (fictitious name) was taken to Prosper Hospital in Recklinghausen. Her
doctors removed a malignant tumor from her colon and also removed her spleen. At the beginning of
August, however, they discovered that her tumor had metastasized (spread).
On Tuesday of the past week the 64-year-old homemaker began her first round of chemotherapy.
Diluted in a clear fluid are two cellular poisons entering her veins through an IV. "This is a complete
nightmare for me," said Frau Meyer. "I never thought that I would one day develop cancer. But I hope
that I will become better. They are making so much progress with chemotherapy." (Die sind ja immer
weiter mit der Chemotherapie.)
At the Clinical Center of the University of Munich one scientist does not share her optimism.
Epidemiologist Dieter Hoelzel, 62, says that "as far as survival with metastatic cancer of the colon,
breast, lung and prostate goes, there has been no progress in the past 25 years." He has documented
the outcome of patients treated since 1978 in and around Munich, according to the standard methods of
oncology. These are people suffering from the advanced stages of one of the four major internal
cancers, which annually claim about 100,000 victims in Germany alone. These tumors are the big killers.
If a tumor has metastasized, and can no longer be reached by surgery or X rays, then chemotherapy is
considered the treatment of last resort. For decades, a series of new cellular poisons have been used.
Often drug manufacturers have also demanded astronomically high prices. In exchange, they promise a
"A chance at life!" say large billboards, each about 9 feet high, for the drug Taxotere. The manufacturer
of a competing product recruits patients using the slogan "Taxol –– give yourself a future!" (Taxol - dem
Leben eine Zukunft geben!)
Erika Meyer's physician in Recklinghausen speaks with confidence. Chemotherapy has clearly improved
over the past 20 years, says conventional oncologist Friedrich Overkamp, MD, 47. "A considerable
extension of lifespan" can be attained, he says.
However, the latest figures from the cancer registry of the University of Munich do not confirm that view.
Survival rates have not improved over the past decades. Today's patients die just as fast of their cancer
as their fellow sufferers did 25 years ago. While the statistical curve for colon cancer shows a slight
improvement, the survival rate for breast cancer actually fell over the course of the years. These
fluctuations probably mean nothing, said Dr. Hoelzel, except the accidental ups-and-downs of statistics
without any real significance. However, he fears that the systematic expansion of chemotherapy for
cancer of the breast could be responsible for the decline of the survival rate.
These statements from the Munich epidemiologist explicitly do not apply to the chemotherapy of
Hodgkin's and non-Hodgkin's lymphoma, leukemia, sarcoma, and testicular cancer. These diseases can
be cured in some cases in an almost spectacular way. Hoelzel's verdict also does not apply to
chemotherapy that is used to shrink tumors before surgical intervention (neoadjuvant chemotherapy,
ed.) or to destroy stray tumor cells after an operation (adjuvant chemotherapy, ed.)
But experienced clinicians agree that the balance tips against chemotherapy when it comes to treating
solid tumors in advanced stages. Gerhard Schaller, MD, 52, a gynecologist at the University of Bochum,
states: "For the survival of women with advanced breast cancer, chemotherapy previously brought them
practically no benefit - a lot of noise about nothing."
Wolfram Jaeger, MD, 49, Director of Gynecology at the State Clinics of Düüsseldorf, has had similar
experiences. "Chemotherapy gave, and gives, no successes. Enormous numbers of women are treated,
without proven benefit (ohne dass ein Nutzen tatsäächlich bewiesen wääre). If we told this to the
patients, however, they would totally despair."
Millions of patients over the past 50 years have undergone chemotherapy. The first patient with an
advanced lymphosarcoma (non-Hodgkin's lymphoma, ed.) was treated with mustard gas by US
physicians in 1942. The tumor shrank in an almost miraculous way. This effect disappeared after three
months and the patient died. Nevertheless, this temporary success rang in the era of chemotherapy
against cancer suffering.
The progress of chemotherapy lies mostly in the fact that it lessens the suffering that it has provoked.
Cytotoxic drugs are cellular poisons that intervene in a different way in the proliferation of cells. Because
tumor cells divide more frequently than most other body cells, tumors and metastases are particularly
susceptible to such drugs. Tumors can shrink, and, every now and then, they disappear even
completely. However healthy cells, which divide rapidly, can also be damaged, including cells of the hair
follicles and the blood forming cells of the bone marrow.
The question [of whether or not chemotherapy really extends life, ed.] can probably no longer be
answered. In clinical studies the manufacturers always compare their new drugs with older cellular
poisons. There are no control groups that are given no treatment at all. In order to be allowed onto the
market, it suffices to achieve a "statistically significant" advantage in one small group of hand-picked test
subjects vs. those treated with some already approved cellular poison.
These drugs are all but harmless. Some of the chemotherapeutic drugs led to the premature death of
patients within weeks of their use and were removed from the market. Other patients were put through
hell. These patiens lost their hair, appetite and had to through and were plagued with a weakend system
and serious systemic infection. On top of that, some of the MD’’s were starting to doubt these cytoxic
drugs could not do much more than temporarily shrink the tumors.
The late Klaus Thomsen, MD, long-time director of gynecology of the University Clinic Hamburg-
Eppendorf, explained in September 1985, at an international congress in Berlin: "It gives us pause to
think, that increasing number of doctors say that they would not use such a therapy on themselves.
Ten years later, the epidemiologist Ulrich Abel, PhD, of the University of Heidelberg, put the entire
usefulness of chemotherapy in doubt. For over a year, this scientist reviewed several thousand
publications on chemotherapy. He concluded that "for most internal cancers no proof exists that
chemotherapy, especially the increasingly high dose variety, increases life expectancy or improves
quality of life."
Notable oncologists agreed: the expansion of chemotherapy could not stop that. But because physicians
did not want to admit to their patients that they were completely defenselessly against cancer, this
poisonous cure became one of the dogmas of medicine.
That ‘‘benefits' all participants: "The physicians are happy that they have something they can offer, the
patients are happy, that they can take something, and the industry is happy," say the Düüsseldorf
Progress mainly consists in reducing the side effects that are caused by the drugs themselves. Earlier,
these cellular poisons weakened patients to such an extent that they had to be supervised in the
hospital. Now, however, methods of reducing hair loss, appetite loss, diarrhea and blood clots lie at
hand. Many chemotherapies can even be carried out on an outpatient basis. Now, explains the
oncologist from Reckinghauser, I can even put carpets in my practice.
Each quarter, oncologist Friedrich Overkamp uses 1.5 million Euro worth of medicines on his 1,100
cancer patients. Nationwide (in Germany) the use of the cytotoxic drugs between August 2003 and July
2004 added up to 1.8 billion Euro –– an increase of 14 per cent compared to the previous year. (Note:
the Euro is currently worth around $1.30).
Monoclonal antibodies, which can recognize cancer cells more specifically, are the latest market drivers.
Again, the drug manufacturers envison a breakthrough. Nevertheless, in this situation as well, clear
proof is lacking that the lifespan of incurably ill cancer patients is truly extended. Meanwhile, competition
from the new monoclonal antibodies leads to a situation in which cellular poisons are pushed more
aggressively in the market.
For decades pharmaceutical manufacturers brought more new cytotoxic drugs to market; in the
seventies there were just five, but in the nineties approximately 25 new drugs were approved. "If each of
these signified some small progress," said Munich epidemiologist Hoelzel, "then this should have led to
remarkable improvements over the past decades. However, we do not see that reflected in our cancer
It is also difficult to find proof of a survival advantage in the thousands of reports from the drug industry.
For metastatic breast cancer there are only about ten studies that suggest that a cytotoxic drug 'cocktail'
extends life, when compared to another such mixture. Because, however, thousands such comparative
studies have been performed, Heidelberg epidemiologist Abel argues that "statistically remarkable
differences in a substantial number of studies are simply due to an expected coincidence."
The proponents of chemotherapy refer particularly to two influential works. In the first of these, French
researchers studied 724 female patients who had metastatic breast cancer. The three-year survival rate
after diagnosis increased from 27 per cent (for those treated between 1987 and 1993) to 43 per cent
(1994 to 2000).
However, the epidemiologist Hoelzel attributes this apparent improvement to a shortcoming in sampling
methodology. In the period 1994 to 2000, metastasized breast cancer tended to be more promptly
recognized than it was in the earlier cases (1987-1993). Because the illness had not progressed so far at
first diagnosis, life expectancy was much greater. This gave the illusion of an apparent increase in
survival time, although of course the apparent improvement in survival rates was not the result of any
Defenders of chemotherapy also cite a study from the University of Texas, Houston, published in August
2003. In this study, the five-year survival rate of women with metastasized breast cancer improved
continuously over the years 1974 to 2000, from 10 per cent to 44 per cent. This article also contained an
overview of all the cytostatic drugs, which the authors claimed had made this alleged progress possible.
However, in the study in question women both with and without metastases were mixed together for
comparison. The groups from more recent time were distorted by the inclusion of more female patients
who had more favorable prognoses. The authors of this celebratory article actually admit that in a hidden
sentence (in einem versteckten Satz).
"There is no systematic documentation at all," says Hoelzel of such "trick research" (Trickforschung).
"That is the great deficiency of cancer medicine," complains Dr. Hoelzel. Meanwhile, with his demand for
clean scientific proof, critic Hoelzel will hardly be allowed to shake up the industry.
Because the industry already manages very well without any proof of the utility of drugs for patients with
NOTE: The original German version can be found on the Internet at:
Web Page Updated September 5, 2009