Scary article--mentioning the "dark side of Herceptin"w stats cardiotoxicity/brnmets

[Lani]

1: Breast Cancer Res Treat. 2007 Jul 19; [Epub ahead of print]
Cardiotoxicity and incidence of brain metastases after adjuvant trastuzumab for early breast cancer: the dark side of the moon? A meta-analysis of the randomized trials.

Bria E, Cuppone F, Fornier M, Nisticò C, Carlini P, Milella M, Sperduti I, Terzoli E, Cognetti F, Giannarelli D.
Department of Medical Oncology, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy, emiliobria@yahoo.it.
Background In five randomized clinical trials (RCTs), adjuvant trastuzumab (T) for early stage breast cancer with human epidermal growth-factor receptor-2 over-expression/gene-amplification has shown to decrease the risk of both recurrence and death. The issue regarding the long-term safety profile of such drug is still open; in particular, questions remain about long-term cardiotoxicity, and specific patterns of relapse such as brain metastases (BM). In order to quantify the magnitude of these two risks, and then balance those with the survival outcome, a literature-based meta-analysis was performed. Methods All phase III trials were considered eligible. A literature-based meta-analysis was accomplished, and event-based relative risk ratios with 95% confidence interval were derived. A fixed- and a random-effect model according to the inverse variance and the Mantel-Haenzel method were applied. Heterogeneity test was applied as well. Absolute differences (AD) and the Number of patients Needed to Treat or to Harm (NNT/NNH) were calculated. Safety end-points were: (1) Chronic Heart Failure (CHF) grade III-IV rate, (2) Significant reduction of left-ventricular-ejection-fraction (L-FEV) rate and (3) BM rate. In order to quantify the magnitude of the significant benefit already found in the original RCTs, Efficacy end-points were: (1) disease-free survival (DFS) and (2) overall survival (OS). Results Five RCTs were gathered (11,187 patients); at an average 2-years follow-up, all data was available for the safety and efficacy end-points, while three RCTs reported results for BM analysis (6,738 patients). When considering RCTs with trastuzumab administered for 1 year, a significant increased risk of grade III-IV Congestive Heart Failure (CHF) was found in the T-arm, with an AD of 1.61% (p < 0.00001), which translates into 62 treated patients required to harm one (NNH). When considering the asymptomatic L-FEV reduction, a significant increased risk of grade significant L-FEV reduction was found in the T-arm, although significantly heterogeneous, with an AD of 7.20% (p < 0.00001), which translates into 14 NNH. The incidence of BM was significantly higher in the T-arm, without significant heterogeneity, with an AD of 0.62 (p = 0.033), which translates into 161 NNH. The DFS, DDFS, and OS were significantly better in the T-arm, with an AD of 6.00, 4.80 and 1.96%, which translates into 16, 21 and 51 NNT, respectively. Conclusions The overall outcome results show that trastuzumab is one of the most important discoveries in oncology. Nevertheless, the biological activity of trastuzumab needs to be investigated more extensively to explore both long-term safety and specific relapse patterns.
PMID: 17638068 [PubMed - as supplied by publisher

The good news is they don't prove causation of brain mets. Will have to look further at the article to see if they took into account that herceptin treated patients may just live longer and thus have time to develop brain mets which would have developed eventually in the nonherceptin treated patients who died before they happened (or got big enough to give symptoms)

Also, at least they did put numbers on it ie, for every 161 persons treated with herceptin you may have had brain mets which otherwise would not have occurred if herceptin had not been given and although every 14th patient treated may have gotten symptomatic heart failure that they otherwise might not have had, you had to treat 64 to get asymtomatic heart toxicity (which by other reports is treatable and reversible)

Perhaps better some numbers than no numbers (and only one's imagination which is usually worse! )

[BonnieR]

Translation please???

[Hopeful]

Lani,

Thanks for putting the numbers in to understandable terms for us math phobes. Seems like even the best treatment can be a two-edged sword. To put another spin on it, looks like my chance of distant recurrence anywhere in the body (w/o Herceptin) is estimated by Oncotype dx at 1 in 3 or 1 in 4; but my chance of getting brainmets specifically with Herceptin is 1 in 161. Seems like a reasonable risk, all things considered.

Hopeful

[Lani]

Herceptin has made an incredible improvement in the survival statistics of those with her2+ breast cancer, but it comes with a cost (the cost is FAR
FAR LESS THAN THE BENEFIT when looking at large numbers of patients, but can be important if any one patient is one of those minorities who suffers from either heart failure due to herceptin or brain mets, which may not be DUE to herceptin, but are found more frequently in those treated with herceptin than in those who are not)

They tried to put numbers on these risks based on combining the many clinical trials that took place which allowed herceptin to get FDA approval:

What I posted before:
The good news is they don't prove causation of brain mets. Will have to look further at the article to see if they took into account that herceptin treated patients may just live longer and thus have time to develop brain mets which would have developed eventually in the nonherceptin treated patients who died before they happened (or got big enough to give symptoms)

Also, at least they did put numbers on it ie, for every 161 persons treated with herceptin you may have had brain mets which otherwise would not have occurred if herceptin had not been given and although every 14th patient treated may have gotten symptomatic heart failure that they otherwise might not have had, you had to treat 64 to get asymtomatic heart toxicity (which by other reports is treatable and reversible)

Perhaps better some numbers than no numbers (and only one's imagination which is usually worse! )

"The DFS, DDFS, and OS were significantly better in the T-arm, with an AD of 6.00, 4.80 and 1.96%, which translates into 16, 21 and 51 NNT respectively"--This means they only had to treat 16 patients for two years to show an improvement in disease free survival in one, 21 patients for two years to see increased distant disease free survival ie, mets, in one and 51 patients to see an increased overall survival, as I understand it. Hopefully as results mature with longer follow-up of patients the benefit wil show itself even more strikingly.
Their Conclusion was: The overall outcome results show that trastuzumab is one of the most important discoveries in oncology.
But they hedged and said we need to understand how it works better in order to decrease side effects so that the risk/benefit ratio is even more
impressive.
Hope this helped.

[Leslie's sister]

Lani:

Thank you for the translation. I so appreciate your posts but know that I have to stop and REALLY read them to interpret them correctly. It was nice being able to read your translation.

Thanks again for your informative posts.