Researchers Ponder Shorter Course of AI therapy

[Hopeful]

I thought this excerpt from the "Interactive Dialogue Session: Clinical Considerations and Debates in Adjuvant Therapy," a panel discussion by Adam M. Brufsky, MD, PhD, Michael Gnant, MD, Matthew R. Smith, MD, PhD, was worth posting:

Adam M. Brufsky, MD, PhD:
In North America, clinicians tend to treat early breast cancer patients with endocrine therapy for 5 years. However, in the ABCSG-12 trial, the patients with hormone-responsive, early-stage breast cancer were treated for only 3 years.Why?

Michael Gnant, MD:
This is a very good question. Because ABCSG is an academic trialist group, the studies are usually built one after the other. The predecessor trial of ABCSG-12 was ABCSG-5, which showed that 3 years of goserelin plus 5 years of tamoxifen—the standard durations for these therapies—was significantly more effective for adjuvant treatment of premenopausal patients with stage I/II breast cancer compared with 6 cycles of
cyclophosphamide, methotrexate, and fluorouracil.This earlier trial established that endocrine therapy benefits patients with early-stage breast cancer. In ABCSG-12, women were randomly assigned to receive goserelin 3.6 mg subcutaneously every 28 days plus tamoxifen 20 mg/day orally or anastrozole 1 mg/day orally with or without zoledronic acid 4 mg intravenously every 6 months for 3 years. The AI (ie, anastrozole) could not be used alone without ovarian function suppression. As such, we would have had to increase the duration of ovarian function suppression to 5 years, which for a variety of reasons we did not want to do, or switch all AI patients back to tamoxifen during Years 4 and 5, which would have made the statistical analysis very complicated. My colleagues and I decided that we would take the risk and offer patients a limited treatment duration of 3 years. Although these treatments are better tolerated than chemotherapy, they are not without adverse events. Limiting the duration of endocrine therapy holds value, particularly for younger women. I believe that the overall outcome of the trial makes it very difficult to claim that 5 years of AI treatment would have been more effective than 3 years. The data revealed 3-year disease-free survival rates of 92.8% in the tamoxifen group vs 92.0% in the anastrozole group.

Adam M. Brufsky, MD, PhD:
I would like to focus on this issue. Clearly, this large trial provides data assessing 3 years of endocrine therapy. Based on these findings, can one make the argument that it is reasonable to consider 3 as opposed to 5 years of endocrine therapy?

Michael Gnant, MD:
To firmly draw a conclusion, this issue needs to be tested prospectively. However, the data do suggest that 3 years of therapy may be sufficient. All other endocrine interventions except for tamoxifen were never really proven to produce better outcomes with a 5-year duration. Studies of tamoxifen defined the standard duration of 5 years based on better efficacy compared with 2 or 3 years of treatment. This was then extrapolated to all other endocrine interventions. However, there is evidence to suggest that shorter durations of AIs may be sufficient.

(emphasis added)

Food for thought.

Hopeful

[Lien]

Can I post this on the Breast Cancer List? There are several women who have severe AI side effects.

Jacqueline

[Hopeful]

Jacqueline,

I don't see why not.

Hopeful

[Montana]

Two and a half years was all I could stand of Arimidex. This is good news.

[Hopeful]

I have been pondering a shorter course of AI's for myself, especially since I have begun treatment for severe atrophic vaginitus resulting from estrogen deprivation. Seeing this study designed and conducted by academics, not pharmaceutical companies, with such a dramatic outcome, gives me confidence.

Hopeful

[Laurel]

Thanks, Hopeful, boy do I ever hope they change the protocol for A.I's! Really hate the stuff!

[Becky]

However - the 3 yr survival stats were stats that were dervived only from the 3 yr trial. Once the trial was done, that was it. What happened to these women in year 4 and 5 (when compared to counterparts who continued on hormone therapy). What were the stats on yr 4 versus women who were continuing therapy. Also, what was the comparison overall as all women took Lupron or Zoladex to shutdown the ovaries which may not happen in "real life" (especially to young women who are taking Tamoxifen).

Shutting down the ovaries in premenopausal women is a boon to survival (prior to Tamoxifen, removing ovaries greatly assisted survival and was commonly done - at least on women with mets).

As many of you know, the 100+ month stats on taking 5 yrs of Arimidex vs Tamoxifen is impressive. I wonder how 3 yrs will stack up (even though you are not comparing apples to apples since the 3 yr women also had ovarian suppression and the 5 yr women did not).

Also, if 3 yrs is worse, is that because they allowed premenopausal women's ovaries to pump out the estrogen again (with no added protection of Tamoxifen)? So many questions between both studies.

[Hopeful]

The discussion I posted is in reference to the article,

"Endocrine Therapy plus Zoledronic Acid in Premenopausal Breast Cancer" from the February 12, 2009 NEJM. Dr. Gnant was one of the authors.

The full text of the NEJM article appears here: http://content.nejm.org/cgi/content/full/360/7/679

Dr. Gnant's comments above go to this portion of the article:

"The results of our study showed that in premenopausal women with early breast cancer, treatment with anastrozole and treatment with tamoxifen were associated with similar rates of disease-free survival. The addition of zoledronic acid to adjuvant endocrine therapy increased the rate of disease-free survival, as compared with endocrine therapy alone. At a median follow-up of 47.8 months, 821 of 904 patients who received endocrine therapy alone (90.8%) were free of disease, and 878 of 904 patients (97.1%) were alive; in the cohort of patients who received zoledronic acid, 845 of 899 patients (94.0%) were disease-free and 883 of 899 (98.2%) were alive. The absolute difference in disease-free survival was 3.2 percentage points, favoring the patients who received zoledronic acid as compared with the patients who did not receive zoledronic acid (P=0.01). This difference is similar to the 5-year absolute difference in disease-free survival observed in trials comparing tamoxifen with aromatase inhibitors in postmenopausal women with early breast cancer.5,28 These outcomes add to the growing body of data showing that subgroups of patients with low-risk or intermediate-risk, endocrine-responsive early breast cancer can be spared the adverse events of cytotoxic therapy after locoregional treatment.29 In our study, treatment with goserelin was given for 3 years, on the basis of the outcomes in a previous trial (the Austrian Breast and Colorectal Cancer Study Group trial 5).10
Although the duration of endocrine therapy in premenopausal patients varies internationally (i.e., from 2 to 5 years), the data from ABCSG-12 indicate that ovarian suppression with endocrine therapy for 3 years can produce excellent outcomes in a population with low-to-intermediate risk. The estimated number needed to treat to prevent disease progression in 1 patient in the intention-to-treat cohort was 31 in the group of patients who received zoledronic acid at a median follow-up of 47.8 months. In contrast, in a meta-analysis of taxane therapy in postmenopausal women with early breast cancer, the numbers needed to treat to prevent disease progression in 1 patient were 28 with the use of paclitaxel (with a median follow-up of 60 to 69 months) and 31 with the use of docetaxel (with a median follow-up of 43 to 60 months).30 Thus, the addition of zoledronic acid to endocrine therapy is consistent with the number needed to treat for cancer therapies that in the past have caused a shift in treatment standards. "

In the authors' response to letters to the editor concerning the article, it was reiterated:

"according to St. Gallen and National Comprehensive Cancer Network guidelines, goserelin plus tamoxifen is an accepted treatment for premenopausal patients with endocrine-responsive breast cancer, and luteinizing hormone–releasing hormone agonists alone are associated with a strong trend toward reduced rates of recurrence and death.1 In the ABCSG-12 study, the selection of 3 years of endocrine therapy was based on the findings of the ABCSG-5 trial (ClinicalTrials.gov number, NCT00309478 [ClinicalTrials.gov] ) (which examined 3 years of goserelin, then 5 years of tamoxifen).2 However, 5 years of continuous endocrine therapy may not be necessary in this low-risk population, since it would be difficult to improve the 98.2% 4-year overall survival achieved in the group receiving zoledronic acid in the ABCSG-12 trial. We agree that long-term follow-up of SOFT and Triptorelin with Exemestane on Tamoxifen (TEXT) (NCT00066703 [ClinicalTrials.gov] ) may provide more definitive guidance on the use of aromatase inhibitors in premenopausal patients with breast cancer. "

Hopeful

[sarah]

Here's a stupid question because I've now been on Herceptin and Femara for 5 years and I know I'm going to be taken off Herceptin soon and wondering about the Femara.
Why does one stop taking an IA?
Do they stop helping at that point?
Is the cancer suppose to no longer be estrogen positive?
Are the side effects so bad?
Just wondering. Despite all the negative side effects, I feel safer, perhaps incorrectly, continuing to take both drugs.
Curious to know since I see the big onc next week
what a disease!
sarah

[Hopeful]

Sarah,

The reason to stop taking AI's is that it is believed that resistance develops with the length of exposure. There have been studies performed which show (in the lab) that ER+ cells can adapt to a low ER environment, and begin growing again. I read a few years ago about a European trial of an alternative regimen of AI therapy, with three months on and three months off, to see if intermittent ER suppression worked better than constant suppression. I have not seen anything about the trial since, and have often wondered if it came off. I have posted a few articles in the articles forum about the sucess some have had in resensitizing ER+ bc to AI's by using ER therapy.

Everyone is different, and some tolerate these drugs better than others. The greatest crime, IMO, is that there are no studies done with trying to adjust dosing to the individual - they are rxed as a "one size fits all," with patients weighing 98 pounds getting the same dose as those that weigh 300 pounds. Perhaps if the dosage were adjusted better, the side effects would be less severe and patients would not be craving an end to the treatment.

Hopeful

[sarah]

thanks Hopeful,
I'll bring it up to the onc. You're right about the weight issue and it is strange that it is a one size fits all. I gained 15lbs during chemo (taxol) and haven't lost it so I'm now nearly 140lbs! so I suppose I fit the dosage. The worst side effect for me is bone loss - the hot flushes, weird hand/feet stuff I can deal with luckily.
thanks again
sarah

[DianneS]

Interesting. I feel like a yo-yo. One day I think I should try AI's. The next I'm thinking I've had enough!

My onc is suggesting maybe we'll try couple years of Tamoxifen then follow it with an AI. I could not tolerate Arimidex; it caused nausea daily.

What other side effects do AI's possibly cause? Sarah, you mentioned 'weird hands and feet' ?? What else can one expect from these wonder drugs?

Diannes

[AlaskaAngel]

This article is in regard to the question of the development of resistance to aromatase inhibitors and possible use of estradiol to deal with that problem, and although it is about use for metastatic disease, it follows the earlier discussion in this thread.

To access the article you would have to follow the instructions provided for this:

http://www.oncologystat.com/news-and...Cancer_US.html

[Hopeful]

Here is a link to another article I posted on the same study that Alaska Angel is posting on above, with no link to follow: http://her2support.org/vbulletin/sho...eferrerid=1173

Hopeful