Receiving 3 to 5 years of bisphosphonate treatment after surgery and chemotherapy for early-stage breast cancer doesn’t improve survival any more than receiving 2 years of bisphosphonate treatment, according to a large study.
The research was published online on June 24, 2021, by the journal JAMA Oncology. Read the abstract of “Prognosis of Patients With Early Breast Cancer Receiving 5 Years vs 2 Years of Adjuvant Bisphosphonate Treatment: A Phase 3 Randomized Clinical Trial."
Bisphosphonates are medicines used to prevent or treat osteoporosis. They do this by limiting the activity of certain bone cells, called osteoclasts, that contribute to the bone weakening and breakdown that leads to osteoporosis.
Previous research has strongly suggested that bisphosphonates also may help stop breast cancer from spreading to the bones by making it harder for breast cancer cells to grow in bones.
Zometa (chemical name: zoledronic acid) is the bisphosphonate doctors most commonly prescribe to reduce recurrence risk (the cancer coming back) after surgery and chemotherapy for early-stage breast cancer with a high risk of recurrence.
Zometa is given by intravenous infusion — which means it is delivered directly into your bloodstream through an IV or a port — every 3 to 6 months, depending on the length of treatment.
Current breast cancer treatment guidelines say postmenopausal women who receive chemotherapy after surgery for early-stage breast cancer with a high risk of recurrence should also receive 3 to 5 years of bisphosphonate treatment after surgery.
Still, it’s not clear how many years of bisphosphonate treatment is best.
So the researchers did this study to see if there were any differences in survival between women who receive 2 years of bisphosphonate treatment after surgery and women who receive 5 years of bisphosphonate treatment after surgery.
About the study
This German study, called the SUCCESS A trial, included information about 2,987 women diagnosed with early-stage breast cancer with a high risk of recurrence. The characteristics that gave the breast cancer a high risk of recurrence were:
- cancer in the lymph nodes (lymph node–positive)
- larger tumor size
- hormone-receptor-negative breast cancer
- grade 3 tumor
- a woman diagnosed at age 35 or younger
All the women had surgery to remove the breast cancer.
About half the women were older than 53 and half were younger. About 58% of the women were postmenopausal.
The researchers first randomly assigned the women to one of two chemotherapy regimens:
- three cycles of fluorouracil, Ellence (chemical name: epirubicin), and Cytoxan (chemical name: cyclophosphamide), followed by three cycles of Taxotere (chemical name: docetaxel)
- three cycles of fluorouracil, Ellence, and Cytoxan, followed by three cycles of Taxotere and Gemzar (chemical name: gemcitabine)
A previous analysis of the study found that adding Gemzar to the chemotherapy regimen didn’t improve outcomes.
After the women completed chemotherapy, the researchers again randomly assigned the women to one of two groups, each taking Zometa for different time periods:
- 1,540 women received Zometa for 5 years: 4 mg every 3 months for 2 years, followed by 4 mg every 6 months for 3 years
- 1,447 women received Zometa for 2 years: 4 mg every 3 months for 2 years
The researchers followed half the women for more than 35.4 months and followed half for shorter periods of time.
Overall, when comparing the two Zometa treatment groups, the researchers found no difference in:
- disease-free survival: how long the women lived without the cancer coming back
- overall survival: how long the women lived whether or not the cancer came back
- distant disease–free survival: how long the women lived without the cancer coming back in a part of the body away from the breast, such as the bones or liver
- bone recurrence–free survival: how long the women lived without the cancer coming back in the bones
This means that 2 years of Zometa offered the same survival benefits as 5 years of Zometa.
The researchers looked to see if women who were postmenopausal might get more benefits from 5 years of Zometa compared with 2 years of treatment. But the results were the same: There was no difference in any of the survival figures between premenopausal women and postmenopausal women in the two Zometa treatment groups.
The researchers also looked to see if side effects caused by Zometa were different in the two treatment groups.
Women treated with 5 years of Zometa were more likely to have side effects compared with women treated with 2 years of Zometa:
- 46.2% of the women treated with 5 years of Zometa had at least one side effect
- 27.2% of the women treated with 2 years of Zometa had at least one side effect
Women treated with 5 years of Zometa also were more likely to have more severe (grade 3 or 4) side effects:
- 7.6% of the women treated with 5 years of Zometa had a severe side effect
- 5.1% of the women treated with 2 years of Zometa had a severe side effect
In both Zometa treatment groups, the most common side effects were:
- bone pain
- joint pain
Still, these side effects were more common in women treated with 5 years of Zometa:
- 8.3% of the women treated with 5 years of Zometa had bone pain compared with 3.7% of the women treated with 2 years of Zometa
- 5.1% of the women treated with 5 years of Zometa had joint pain, compared with 3.1% of the women treated with 2 years of Zometa
“The results of this phase 3 randomized clinical trial indicate that extending the zoledronate treatment beyond 2 years does not improve the prognosis of high-risk patients with early breast cancer receiving chemotherapy, suggesting that the currently recommended bisphosphonate treatment duration of 3 to 5 years could be reduced,” the researchers concluded.
“Concerns about adverse effects of prolonged bisphosphonate treatments, such as atypical bone fractures and osteonecrosis of the jaw, as well as results from both preclinical and clinical studies indicating that the benefit of bisphosphonates continues after termination of treatment, are additional reasons to question the necessity of extended bisphosphonate therapy,” they added.
An editorial published at the same time as the study called for reconsidering bisphosphonate guidelines. The editorial writers pointed out that previous studies found bisphosphonates offered only modest benefits and that modern treatments for early-stage breast cancer lead to low rates of recurrence. In this study, recurrence rates were less than 10% in each Zometa treatment group.
“What, if any, is the benefit from adjuvant bisphosphonates? It’s time to reevaluate the guidelines,” the editorial authors wrote.
What this means for you
If you’ve been diagnosed with early-stage breast cancer with a high risk of recurrence and your doctor prescribes bisphosphonate treatment after you’ve had surgery and completed chemotherapy, it’s a good idea to talk to your doctor about this study. If your treatment plan calls for 5 years of Zometa, you may want to ask your doctor if there is a reason he or she recommends 5 years instead of 2 years. You can talk about this study’s results, which found no difference in outcomes between 2 and 5 years of Zometa. You also can discuss how women who took Zometa for 5 years had more side effects.
Together, you and your doctor can develop a bisphosphonate treatment plan that is best for you and your unique situation.
Written by: Jamie DePolo, senior editor
Reviewed by: Brian Wojciechowski, M.D., medical adviser
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