Herceptin Trial Question

[tousled1]

Has anyone heard any results or information on the clinical trial of the 9 week Herceptin infusion?

[Becky]

It is called the FinHer Study. Herceptin was used with neoadjuvant chemo (with or without Herceptin) for 9 weeks prior to surgery. Here is the study results..



Fin/Her Study
March 2006

A 3-year interim analysis1 of the FinHer (Finland Herceptin) study, published in the February 23, 2006 issue of the New England Journal of Medicine, found that adjuvant treatment with docetaxel (Taxotere) prior to chemotherapy significantly decreases recurrence in women with node-positive or high-risk node-negative early stage breast cancer compared to vinorelbine (Navelbine). A planned subgroup analysis of HER2-positive patients found that adding a nine-week course of trastuzumab (Herceptin) to Taxotere or Navelbine prior to chemotherapy also significantly improved recurrence-free survival.

How was the study done?
This study randomly assigned 1,010 women with node-positive or high-risk node-negative early stage breast cancer to either 3 cycles of Taxotere or Navelbine, followed by (in both groups) three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). Women who were estrogen-receptor positive and/or progesterone-receptor positive were also put on Tamoxifen for 5 years following chemotherapy (approximately 72.5% of patients). All women who had a lumpectomy received adjuvant radiation therapy after chemotherapy (approximately 97% of patients).

There were 232 women with HER2-positive breast cancer (23% of the study population) who were further randomized to receive either nine weekly infusions of Herceptin or no Herceptin. HER2 expression was scored by immunohistochemistry (IHC) and HER2/neu gene amplification was confirmed by chromogenic in situ hybridization (CISH) when IHC findings were scored as 2+ or 3+ (on a scale of 0, 1+, 2+, or 3+).

This is one of several studies looking at Herceptin in addition to chemotherapy in the adjuvant setting. While all reports from interim analyses of these studies favor the use of Herceptin, the optimal length of treatment with Herceptin has not been established. This is the first study to report on the effect of a short course of treatment (less than one year) with Herceptin on patient outcomes.2 Women randomized to Herceptin started their treatment at the same time as Taxotere or Navelbine. By administering Herceptin before FEC, the authors sought to determine whether this schedule would "limit cardiotoxicity and maintain efficacy."3 The primary endpoint of this study was recurrence-free survival.4 The authors of this study plan to release a final analysis of their findings in two years (after five years of follow-up).

The study had a factorial design5 that included the prospective comparison of all HER2-positive patients who were randomly assigned to receive one of the two chemotherapy regimens described above with or without Herceptin. Factorial designs can be appropriate and efficient methodologies to answer multiple research questions in prospective clinical trials. Subgroup analyses in this setting differ from the data mining that occurs when studies 'slice' the population of participants to analyze the effects of interventions among groups with specific characteristics.6

What were the results?
The preliminary results of this study show that women taking Taxotere experienced a 42% reduction in risk of recurrence or death4 compared to women taking Navelbine (8.4% versus 14% recurrence rate, or a 5.6% absolute difference), and a 44% reduction in risk of metastasis (6.6% versus 11.4%, or a 4.8% absolute difference). At this time, there is no observed significant difference in overall survival between the two groups. Women on Taxotere experienced more adverse effects7 than those on Navelbine, and as a result the originally scheduled dose of Taxotere had to be lowered during the course of the study.

Among HER2-positive patients, women who took Herceptin in addition to either Taxotere or Navelbine and chemotherapy experienced a 58% reduction in risk of recurrence or death compared to those not on Herceptin (10.4% versus 23.3%, or a12.9% absolute difference), and a 71% reduction in metastasis (7.0% versus 22.4%, or a 15.4% absolute difference). There was no observed difference in overall survival between these two groups. Women taking Herceptin did not experience significantly more cardiac events than those not on Herceptin.

What are the implications of this study? Taxotere in the Adjuvant Setting The preliminary findings of this study suggest that Taxotere significantly improves recurrence-free survival compared to Navelbine among women with node-positive or high-risk node-negative early stage breast cancer. However, Taxotere was associated with more toxic effects than Navelbine. A significant number of women in the Taxotere group (almost 40%) were diagnosed with neutropenic fever soon after the trial began, leading the study-monitoring committee to recommend a 20% dose reduction.Herceptin in the Adjuvant SettingLength of Herceptin Therapy This is the first time it has been shown that a short (9 week) course of Herceptin can significantly reduce recurrence among women with HER2-positive breast cancer. These results add to the increasing body of evidence confirming Herceptin's efficacy in the adjuvant setting. However, the number of HER2-positive patients randomized within the four separate arms of this study was small5. It is important that larger studies be conducted in order to determine the optimal length of therapy with Herceptin. If it can be demonstrated that a shorter course of therapy preserves efficacy, the implications for patients would be positive in terms of quality of life (by reducing the number of patient visits to the doctor) and in terms of cost. Sequencing of Herceptin Therapy Prior studies have shown that Herceptin can have a harmful effect on the heart, particularly when combined with certain chemotherapy regimens8. This study's findings are very interesting because they suggest that administering Herceptin prior to other therapies with known heart-damaging effects (such as anthracyclines) reduces the risk of adverse cardiac events3. Further follow-up is necessary in order to assess whether the improved safety of this mode of administration is preserved over time. Future studies of Herceptin in the adjuvant setting should explore this mode of administration. The preliminary data from this study on timing of administration of, and length of treatment with, Herceptin are provocative when considered in the context of other recent findings. Four other studies have shown a substantial decrease in relapse among women with HER2-positive early breast cancer who received adjuvant Herceptin in addition to chemotherapy, but the duration of Herceptin use in these trials was much longer (52 weeks on average). Those studies also showed a substantive increase in the risk of cardiac toxicity in women who took Herceptin with or after anthracycline-containing chemotherapy regimens. (For an analysis of these four trials, go to NBCCF Analysis on Adjuvant Herceptin Combined with Chemotherapy in Women with HER2-Positive Early Breast CancerWhat are the limitations of this study?
Because this is an interim analysis and the follow-up period is limited there should be caution when interpreting these results. Since the study's factorial design took into account a prospective analysis of HER2-positive patients who were randomized to treatment with or without Herceptin, the limitations usually associated with a subgroup analysis are not a major concern. However, the number of HER2-positive patients (232) between the 4 arms of the Herceptin study makes it imperative that these findings be confirmed prospectively with a larger study population.

Further follow-up of patients in this study is necessary in order to confirm whether (1) the survival benefits observed for Taxotere over Navelbine hold up over the long term, (2) the safety benefits observed for short-term adjuvant Herceptin therapy hold up over the long term, and (3) whether the Taxotere- and Herceptin-containing regimens will have a significant effect on overall survival in the future.


Footnotes

1.An analysis that compares intervention groups at any time before the trial is formally completed. This type of analysis should be considered preliminary.

2.Previous trials have looked at Herceptin therapy in the adjuvant setting for either one or two years.

3.According to the authors, the principal adverse effects attributable to 12 months of Herceptin therapy given with or after chemotherapy in the adjuvant setting include heart failure, which occurred in 1.7% to 4.1% of women treated with the antibody, and a substantial decrease in the left ventricular ejection fraction (LVEF), which occurred in 10% of Herceptin-treated patients. The risk of cardiac dysfunction with Herceptin treatment increases with the use of anthracyclines. (Slamon, et al., NEJM 2001; 344:783-92 and Perez, et al., JCO 2004; 22:322-9.)

4.Recurrence-free survival was defined as the time from the date of randomization to the date of detection of local, distant, or contralateral invasive breast cancer or death, whichever occurred first.

5.In a trial using a factorial design, participants are allocated to one of a certain number of combinations. In the case of the FinHer study, HER2-positive participants were allocated to (a) Taxotere followed by chemotherapy [n=58], (b) Navelbine followed by chemotherapy [n=58], (c) Taxotere plus Herceptin followed by chemotherapy [n=54], or (d) Navelbine plus Herceptin followed by chemotherapy [n=62].

6.Since the effect of an intervention is evaluated within a defined subset of trial participants (e.g. hormone receptor status), sample sizes within subgroup analyses are often small. Even if the results are statistically significant, these are considered to be hypothesis-generating and therefore require confirmation in randomized, prospective studies.

7.Taxotere was more commonly associated with neutropenic fever (fever due to infections that develop after an individual's white blood cells have decreased), stomatitis, alopecia, toxic effects on the skin, nail problems, allergic reactions, neuropathy, and edema than was Navelbine, which more frequently caused peripheral-vein phlebitis, and elevation in the serum aspartate aminotransferase level.

8.These studies include the NSABP B-31, NCCTG N-9831, and BCIRG 006 trials.





Good luck with your decision on whether to take a Herceptin break or not. Your case is more advanced and I would stay on and switch to the every 3 week regime to give yourself a break but not stop unless cardio problems occur. I hope I haven't overstepped my bounds in giving you my opinion/advice. I only give it out of concern for your well being and future cancer free outcome.

Kindest regards,
Becky

[tousled1]

Becky,

Thanks for the info. And, no you haven't over-stepped your bounds. As you know, I'm seriously considering a break from Herceptin but haven't made up my mind yet. I finish my rads next Friday and maybe I'll feel differently after that's completed. I'm just at a point where I want to feel like a "normal" person. I initially tried the 3 week Herceptin and had serious problems with it and that's why I went to every week. Through all my other treatments I did really well with very few side effects. It seems that Herceptin and I just do not get along together.

[al from Canada]

The results of the Finnish study are not widely accepted because if you compare the sampling size to that of the HERA trial, there's no comparisons. I remember asking a few high-profile oncs about it at San Antonio and they weren't impressed for that reason.

Al

[Christine MH-UK]

Although there is interest in this trial, my oncologist, who seems to be in the know, said flat out that there would be no follow up until after the 2 yr. arm of the HERA trial reported out. Basically there is too much risk: oncologists don't want to undertake a trial only to have HERA's 2 yr arm raise the bar so much that such a study would be pointless. Personally, I think that Hurley's work with herceptin + cisplatin + taxotere -> AC looks better already (over 80% disease-free survival at three years followup in stage III women), although that, too, is small and I would like to see the AC replaced by FEC in the combo.

[Patricia]

tousled1,

I was having the same thoughts about stopping the Herceptin early. I started last December and am considering stopping in Oct. What I agreed with myself, my husband and my doc is that I am 'taking a break' until the 2 year study is out in December. If at that point there is clear scientific proof that the 2 years is better than the 1 (meaning longer is better), then I will start up again. The part I have a hard time with is the randomness of the 1 year protocol. There is no logic or scientific facts behind it at this point. It is merely a number that was picked by the studies because you have to pick a length of time to go with when building the studies. I too am desperate to get back to life. I had 2 diff cancers diagnosed within a month of each other and I really need to get back to life as much as I can for as long as I can. As soon as there is evidence otherwise, I promised everyone I will jump right back into treatment with the Herceptin, but I figured that some women have to take a break for a MUGA and then come back to treatment. So I will be taking a 3 month break and then we will see. Good luck to you and your decision. It is so personal for each of us, you need to do what is best for you.

Best,
Patricia

38, dx July 2005 idc Stage 1, grade 3, 1.6 Her2+/ER+/PR+, Partial Mastectomy, 0 nodes involvement, 4AC (dose dense), 12 Taxol, Herceptin, 36 rads, Lupron, Aromasin. dx thyroid cancer Aug 2005, total thryoidectomy, Radioactive Iodine next week

[snoopy]

IMHO its not just FinHER that is important. N9831 also pointed to an increased benefit of combining herceptin and taxanes. (Thought I'd read something about a ??? synergysitic action of the two but can't find ref at present).

I suppose that at least when the HERA 2 year stats are released, longer term data from the other studies will be available which may help (or indeed hinder) making future plans re studies etc. etc.).

Oh for a "crystal ball" to look at survival data in 10 years time when sorting out treatment plans now.