d.d. 3 juli 2003:

Twee studies, waaronder een Nederlandse studie spreken elkaar tegen in het effect van extra hoge dosis chemo met stamcel transplantatie-ondersteuning in een behandeling van borstkanker. De Nederlandse oncoloog Dr. S. Rodenburg spreekt van een kans op een langere overlevingsduur, overigens marginaal blijkt uit de studie (65% tegenover 59 % overleefde de vijfjaarsgrens, dus niet een definitieve genezing, terwijl een studie gedaan aan de universiteit van Chicago wijst op geen enkel effect op die langere levensduur. Extra hoge dosis chemo bij borstkanker met aanvullend stamcelcellen zou alleen maar de kwaliteit van leven ernstiger aantasten en daardoor moeten worden afgeraden, aldus de onderzoekers uit Chicago. Mede ook omdat de hoge dosisbehandeling drie keer zoveel kost dan de standaard chemo behandeling. € 50.00,- tegenover € 150.000,-- per patiënt op jaarbasis. Beide studies zijn gepubliceerd in the NEJM - New England Journal of Medicin. Hier twee Engelse persberichten hierover, de eerste van Medscape en de tweede van Healthdaynews.

Conflicting Results for High-Dose Chemo With Stem Cell Support for Breast Cancer

Laurie Barclay, MD

July 2, 2003 — Two trials described in the July 3 issue of the New England Journal of Medicine report conflicting results for use of high-dose chemotherapy with stem cell support for the treatment of breast cancer. The editorialist helps explain the differences, such as the higher intensity of therapy in the positive study.

"A number of relatively small, uncontrolled studies have suggested that adjuvant high-dose chemotherapy with hematopoietic progenitor cell infusion could be of benefit for high-risk breast cancer," write Sjoerd Rodenhuis, MD, and colleagues from the Netherlands Working Party on Autologous Transplantation in Solid Tumors. "Clearly, much larger prospective, controlled trials were required to ascertain the efficacy of this treatment."

This study enrolled 885 patients younger than 56 years who had undergone surgery for breast cancer without distant metastases but with at least four positive axillary lymph nodes. Patients were randomized to conventional-dose treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) every three weeks for five courses, followed by radiation therapy and tamoxifen, or to high-dose treatment. The latter was identical except that high-dose chemotherapy (cyclophosphamide 6 g/m2, thiotepa 480 mg/m2, and carboplatin 1,600 mg/m2) with autologous peripheral blood hematopoietic progenitor-cell transplantation replaced the fifth course of FEC. Median follow-up was 57 months.

Actuarial five-year relapse-free survival was 59% in the conventional-dose group and 65% in the high-dose group (hazard ratio [HR] for relapse, 0.83; 95% confidence interval [CI], 0.65 - 1.03; P = .09). Among patients with at least 10 positive lymph nodes, relapse-free survival was 51% in the conventional-dose group and 61% in the high-dose group (HR, 0.71; 95% CI, 0.50 - 1.00; P = .05).

"High-dose alkylating therapy improves relapse-free survival among patients with stage II or III breast cancer and 10 or more positive axillary lymph nodes," the authors write. "This benefit may be confined to patients with HER-2/neu-negative tumors."

In contrast, the second study showed that high-dose chemotherapy and stem cell support may reduce the risk of relapse but does not improve outcome in primary breast cancer patients with at least 10 positive axillary lymph nodes.

"Conventional-dose adjuvant chemotherapy remains the standard of care for such patients," write Martin S. Tallman, MD, from Northwestern University in Chicago, Illinois, and colleagues.

In this randomized study, 540 women with primary breast cancer and at least 10 involved ipsilateral axillary lymph nodes received six cycles of adjuvant chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or the same adjuvant chemotherapy followed by high-dose chemotherapy (cyclophosphamide 6 g/m2 and thiotepa 800 mg/m2 over 4 days) with autologous hematopoietic stem-cell transplantation.

Disease-free survival, overall survival, and time to recurrence among 511 eligible patients were no different in the conventional-dose vs. the high-dose group. Among 417 patients meeting strict eligibility criteria, the time to recurrence was longer in the stem-cell transplantation group than in those who received CAF alone. In the transplantation group, nine patients died of complications related to transplantation and nine developed a myelodysplastic syndrome or acute myeloid leukemia.

Some of the study authors report financial arrangements with Bristol-Myers Squibb, Genentech, Astra Pharmaceuticals, Aventis, Merck, AstraZeneca, Pfizer, and/or Wyeth-Ayerst.

In an accompanying editorial, Gerald J. Elfenbein, MD, from Roger Williams Medical Center in Providence, Rhode Island, discusses the contrasting results of these two studies. In women with 10 or more positive nodes, neither trial showed a difference between the two regimens in overall survival, but both showed reduced relapse rate in the high-dose chemotherapy group.

"Although overall survival may be considered the 'gold standard' for assessing clinical value, it is inappropriate to conclude that a primary strategy yields no benefit if overall survival is not prolonged," he writes. 

He notes that longer follow-up might show differences in survival, that only very large studies could identify subgroups obtaining a survival benefit from high-dose chemotherapy, that covariables may confound the results, and that there was a very large difference in the high-dose chemotherapy regimens used in both studies.

"Relapse after primary therapy remains the most important problem to overcome in high-risk breast cancer," he writes. "High-dose chemotherapy should best be viewed as a launching pad from which to explore new methods of post-transplantation therapy to reduce the probability of relapse."

N Engl J Med. 2003;349:7-16, 80-81

Reviewed by Gary D. Vogin, MD


WEDNESDAY, July 2 (HealthDayNews) -- Two new studies seem to have reached vastly different conclusions on how to best treat aggressive, recurring breast cancer 

The first report, out of Northwestern University's Feinberg School of Medicine in Chicago, concludes that adding high-dose chemotherapy with bone-marrow transplantation to traditional chemotherapy offers little benefit to women suffering from breast cancer. Not only that, but several women on the high-dose regimen died of leukemia or other disorders.

The second study, out of the Netherlands, found exactly the opposite: high-dose chemotherapy and bone-marrow transplantation did improve relapse-free survival for certain patients. 

Both findings appear in the July 3 issue of the New England Journal of Medicine 

A debate has long simmered over whether high-dose chemotherapy might improve the odds for women with aggressive, recurring breast cancer. Because the high-dose treatment destroys marrow, the procedure is accompanied by bone-marrow transplantation. 

Both studies looked at women who had positive lymph nodes and who had undergone surgery to remove the primary tumor. 

The Northwestern researchers randomly assigned 540 women to receive either six cycles of standard chemotherapy or standard chemotherapy followed by high-dose chemotherapy with bone-marrow transplantation. The women were enrolled between 1991 and 1998 and were followed for a median of just over six years. 

After assessing 511 women, the authors found the six-year overall survival rate was 62 percent in the group that received standard chemotherapy alone and 58 percent in the group that received high-dose chemotherapy, a difference not considered statistically significant. 

Also at six years, 48 percent of the patients in the standard group were free of recurrence versus 55 percent in the high-dose group -- again, not a significant difference. 

But, 18 of the women getting the high-dose chemotherapy died. 

The Dutch study looked at 885 women. All patients had five courses of a standard chemotherapy, followed by radiotherapy and tamoxifen, while one group also received high-dose chemotherapy with bone-marrow transplantation. 

The five-year, relapse-free survival rates were 59 percent in the conventional group and 65 percent in the high-dose group. Among women with at least 10 positive lymph nodes, the recurrence-free survival rates were 51 percent in the conventional group and 61 percent in the high-dose group. 

Just as the studies reach different conclusions, experts too are divided on their significance. 

"When I look at the overall evidence [from these and other studies], I don't think high-dose chemotherapy is an accepted standard regimen," says Dr. Jeffrey Abrams, associate chief of the clinical investigations branch at the National Cancer Institute (news - web sites). "It may still be an area of investigation" for the future, he adds, "but with that said, I don't think it should be part of standard treatment." 


However, Dr. George Somlo, associate director of high-dose chemotherapy in the division of medical oncology and therapeutics research at City of Hope National Medical Center, understandably has a different perspective.

"The study from the Netherlands is the one I would consider more meaningful," he says. "The Dutch study to me is a better study in terms of design and credibility. Clearly they found that in those with 10 or more lymph nodes -- high-risk characteristics -- there was a definite advantage, in my mind." 

"Both studies show no difference in overall survival between those that got high dose and those got conventional chemotherapy, so the only thing they show is that there may be a decrease in relapse rates in those who got the high dose," says Dr. Avi Barbasch, an associate clinical professor of medical oncology at the Mount Sinai School of Medicine in New York City. "It took a little bit longer for the disease to come back." 

Another question is whether high-dose chemotherapy with bone-marrow transplantation has been supplanted by other therapies in the years since these studies were begun. 

"For people who have 10 or more nodes, I think the treatment today would be quite different," Barbasch says. Growth factors stimulate the body to make white blood cells. "One of the things that's getting a lot more play is doing it more frequently, dosing weekly or every two weeks with growth-factor support in between so the patient can withstand more intensive treatment," he adds. 

"People were hoping that given how toxic the [high-dose chemotherapy] treatment was that we would see a rather major effect, and the effect that we're seeing is not different than the types of improvements that we've seen by the simple addition of a new drug like Taxol to standard regimens, or a recent study that gave the standard treatment every two weeks instead of every three weeks," Abrams says. "Improvements are in the range of 5 to 10 percent, but those kinds of improvements haven't necessitated these high doses, which are extremely expensive and have severe side effects." 

d.d. 4 juli:

Nadat ik het NFK www.kankerpatient.nl bovenstaande informatie had toegestuurd voor officiële website van het NFK met voorlichting van het KWF - melden zij alleen de Nederlandse studie over hoge dosis chemo bij borstkanker en maken er een positief bericht van. Ik vraag me echt af waarom ze de studie uit Chicago niet vermelden, waarom ze niet vermelden dat de bijwerkingen veel en veel ernstiger zijn dan bij een standaard behandeling en dat ook tijdens de behandeling meer patiënten zijn overleden dan bij een standaard behandeling en waarom ze er zo'n positief bericht van maken. Dit lijkt toch wel sterk op misleiding in voorlichting aan de kankerpatiënt. Leest u a.u.b. ook onze berichtgeving over beide studies hierboven en commentaar van erkende specialisten.

Van de NFK-site:

03/07/2003 

Zwaardere chemotherapie kan helpen bij borstkanker 

Een hoge dosis chemotherapie kan vrouwen met borstkanker helpen. Dat
blijkt uit een groot Nederlands onderzoek naar borstkanker, waarvan de
resultaten vandaag verschijnen in de New England Journal of Medicine. 

Vijf jaar na een standaardbehandeling was 51 procent van de patiënten,
die een sterk verhoogde kans hadden op terugkeer van de ziekte, nog
gezond. Na een hoge dosis chemotherapie was dat percentage 61. 

Het onderzoek werd gecoördineerd door prof. dr. S. Rodenhuis van het
Antoni van Leeuwenhoek ziekenhuis/Nederlands Kanker Instituut. Aan het
onderzoek deden 885 vrouwen mee die waren geopereerd en een matig tot
sterk verhoogde kans hadden op terugkeer van de ziekte. 

Het effect van de hoge dosis chemotherapie op langere termijn (dus op
echte genezing) is nog onzeker, omdat de patiënten daarvoor nog niet
lang genoeg zijn gevolgd. Uit het onderzoek bleek dat de hoge dosis
vooral voordelen biedt voor patiënten met minder agressieve tumoren,
ongeveer 80 procent van alle borstkanker. 

Jaarlijks krijgen ongeveer 10.000 Nederlandse vrouwen borstkanker. Bij
veel patiënten is de ziekte nog in een vroeg stadium en kan die met
operatie en eventuele aanvullende behandeling worden genezen. Een klein
deel van hen heeft al uitzaaiingen naar organen, zoals lever of long, of
naar de botten. 

In die situatie is nog maar zelden genezing mogelijk. Veel patiënten
hebben geen uitzaaiingen op afstand, maar wel uitzaaiingen naar de
lymfeklieren in de oksel. Voor deze groep vrouwen is de kans op genezing
groter wanneer zij naast operatie en bestraling ook nog worden behandeld
met chemotherapie en/of hormonen.

Link bij dit artikel:
http://content.nejm.org/cgi/content/short/349/1/7  Engelstalige
samenvatting van het onderzoek op website NEJM