interim results of Canadian clinical trial w pegylated doxorubicin and herceptin

[Lani]

in metastatic patients--looking good!

Pegylated Liposomal Doxorubicin and Trastuzumab in HER-2 Overexpressing Metastatic Breast Cancer: A Multi-Center Phase II Trial.

Chia S, Clemons M, Martin LA, Rodgers A, Gelmon K, Pond GR, Panasci L.

British Columbia Cancer Agency, Vancouver Cancer Centre; British Columbia Cancer Agency, Fraser Valley Cancer Centre, Surrey BC; Toronto Sunnybrook Regional Cancer Centre; Princess Margaret Hospital, Toronto, Ontario; Schering Canada Inc; McGill University, Jewish General Hospital, Montreal, Quebec, Canada.

PURPOSE: Cardiotoxicity precludes the concurrent use of doxorubicin and trastuzumab. Because pegylated liposomal doxorubicin (PLD) has equal efficacy but significantly less cardiotoxicity than conventional doxorubicin, this phase II study assessed the rate of cardiotoxicity and efficacy of first-line PLD plus trastuzumab in HER-2-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with HER-2-positive, measurable MBC, and a baseline left ventricular ejection fraction (LVEF) >/= 55% were treated with PLD 50 mg/m(2) every 4 weeks for six cycles and weekly trastuzumab (4 mg/kg loading dose then 2 mg/kg thereafter). Cardiotoxicity was defined as symptomatic congestive heart failure (CHF) with >/= 10% decline in LVEF to below lower limits of normal, >/= 15% decline in LVEF without symptomatic CHF, or less than 10% LVEF decline to less than 45%. RESULTS: Thirty women were enrolled, 13 had received prior adjuvant anthracyclines. A median 5.5 cycles of PLD were administered. Mean baseline LVEF was 62.8%, 59.5% after cycle four, and 58.3% after cycle six. Three patients (10%) developed protocol-defined cardiotoxicity. No patients developed symptomatic CHF. Response rate was 52%, with an additional 38% stable disease rate. At a median follow-up of 13.9 months, the median progression-free survival was 12.0 months; median overall survival has not yet been reached. The most common adverse events were grade 3 hand-foot syndrome (30%) and grade 3/4 neutropenia (27%). CONCLUSION: The combination of PLD and trastuzumab is a well tolerated and active regimen in HER-2-positive MBC. Cardiotoxicity was observed, but limited to asymptomatic declines in LVEF. Further evaluation of this combination is warranted.

PMID: 16682726 [PubMed - as supplied by publisher]

[rosie]

While this looks like a very interesting study, I don't seem to see that the study showed that adding herceptin was beneficial? Did I miss that? I understand it showed that heart toxicity was minimal but I still don't understand if adding herceptin was helpful.

[Lani]

The fact that 52% responded with an additional 38% experiencing stable disease is truly remarkable in the setting of metastatic disease--that amounts to 90% of patients not progressing while on the combination!!!! So obviously herceptin is making a great difference and doxil is a good combination with it(and it is even possible to take doxil without terrible cardiotoxicity in patients who previously were treated with an anthracycline--usually toxicity is dose-related and there is a life-time limit to how much anthracycline that can be given according to the papers I have read.

When no effective treatment is given, the average life expectancy of her2 positive breast cancer patients is 1 year after distant recurrence (from Dr. Slamon's talks) yet these patients had an average 12 month progression free survival (at a mean 13.5 months into the study--as the study continues with longer follow-up those that are doing well may scewed the results into even longer progression free survival figures) and they had not yet reached median overall survival (as people were living sufficiently longer that not enough of them had died during the study to come up with figures!!!!

Why would the researchers do a study of doxil with and without herceptin at this time, when all studies in Europe with HERA which allowed "any reasonable chemotherapy regimen" plus Herceptin (and there was quite a variety of them!) showed the recurrence rate to be about 50% less with Herceptin than without?

I am certain that if the results of studies of doxil were equally good (90% of patients were either improved or stable) there would have been lots of news stories about it. Feel free to look up any doxil monotherapy articles and let me know...

Hope this helped!

[heblaj01]

If the results of this trial are confirmed in a phase 3 trial with a much larger number of patients I believe that it will mean a big improvement over the results of chemo+herceptin phase 3 trials reported at the end of 2005.

The reason for this lies in the way the statistics were reported in 2005.
The 50% reduction in recurrence rate was a relative figure not an absolute figure. The absolute figure was much lower.

The important statistic to watch, beside quality of life, is overall survival duration (more significant than disease free survival without longer life expectancy)

[Christine MH-UK]

I think we need to be careful when comparing this trial to HERA and the BCIRG trials on early BC patients since this was a trial on patients with metastatic cancer. As a treatment for stage IV women who have already had anthracyclines it looks like a big step forward.

[rosie]

"The fact that 52% responded with an additional 38% experiencing stable disease is truly remarkable in the setting of metastatic disease--that amounts to 90% of patients not progressing while on the combination!!!! So obviously herceptin is making a great difference and doxil is a good combination with it(and it is even possible to take "

Gee, I find it hard to jump to this dramatic conclusion with a study of only 30 patients, where the sites of metastases are not discussed and the number of prior treatments is not mentioned. Call me a cynic, but I have been down this metastatic path for almost 7 years now and if I've learned anything, it's to go with my gut not necessarily the study numbers. If I had done that, I would have been gone a long time ago.

I was on doxil last year and was jumping at the bit to add herceptin to it. I spoke to many "experts" including a cardiologist at MD Anderson who wrote a book on doxil and cardiac toxicity. He really encouraged me to try it and said if it was his wife, he would recommend that she do it. Eventually, I decided not to after speaking with Dr. Pegram at UCLA and another prominent onc at Dana Farber because they said there just wasn't enough proof to take the risk and if I damaged my heart muscle I would never get into any future clinical trials. I felt this was prudent advice.

Sometimes, you have to look at the big picture when one makes decisions about prolonging life.

Just my 2 cents......I guess we all have to make decisions that feel right for us.