Controversies in Care: New Treatment Considerations for Breast, Bladder Cancer and Pediatric Ewing Sarcoma

SALT LAKE CITY—Bisphosphonates may have a role as an adjuvant breast cancer treatment, cisplatin-based neoadjuvant chemotherapy should be considered for treating bladder cancer, and dose-dense chemotherapy may add benefit for patients with pediatric Ewing sarcoma, according to 3 presentations at the “Controversies in Care” session at the annual meeting of the Hematology/Oncology Pharmacy Association.

Bisphosphonates in Breast Cancer
“We use bisphosphonates commonly in our practice but there are classifications based on whether they contain nitrogen,” said Jared M. Freml, PharmD, BCOP, clinical pharmacy specialist–oncology at Kaiser Permanente in Denver, Colorado, in his discussion on the early and delayed use of bisphosphonates in breast cancer patients.

He explained that clodronate and etidronate are non-nitrogen treatments that bind to the bone surface. As they accumulate there, osteoclasts break down, resulting in the accumulation of cytotoxic levels. Nitrogen-containing bisphosphonates include pamidronate, ibandronate, risedronate, alendronate, and zoledronic acid (ZA). These treatments also bind to the bone and “are taken up by osteoclast,” resulting in cytotoxic levels. They also inhibit the mevalonate pathway.

“I think it’s smart that we’ve looked at bisphosphonates as possible antitumor agents, as they have demonstrated antiproliferative and proapoptotic activity in cell and animal cultures,” said Freml. In addition, bisphosphonates that contain nitrogen inhibit the migration and invasion of tumor cells.

“Sequencing might be an important thing to consider as we’re giving these drugs,” he added. Doxorubicin and paclitaxel followed by ZA has shown synergistic antitumor effects, and pamidronate and ZA have been shown to inhibit angiogenesis in mouse models.

Studies that have looked specifically at clinical outcomes for treatment with adjuvant bisphosphonates for patients with estrogen receptor– or progesterone receptor–positive breast cancer, however, have shown mixed results. Whereas in the randomized Austrian Breast and Colorectal Cancer Study Group Trial, 12 of 1803 patients (randomized to 4 treatment arms) showed a significant increase in disease-free survival for those receiving treatments containing ZA compared with hormonal treatment only, the 3360-patient Neo-Adjuvant Zoledronic Acid to Reduce Recurrence (AZURE) trial did not. Neither trial showed a statistically significant increase in overall survival.

In these 2 trials, plus 2 others cited by Freml, there was a significant benefit in bone mineral density at 36 and 60 months for those who received ZA. “I think it’s important that [we] didn’t see any adverse reactions except as expected: flulike symptoms, pyrexia, bone pain, and headache.” The one exception was a higher incidence of osteonecrosis of the jaw in the AZURE trial.

Freml said that although the role of bisphosphonate adjuvant therapy for breast cancer “is evolving,” the optimal administration has yet to be defined, and it is unclear which patient group is most likely to benefit from this treatment. “There are some interesting theories being generated from early studies, but it is difficult to conclude that these are practice changing at this time,” he summarized.

Neoadjuvant Therapy in Bladder Cancer
Surgery is currently considered the standard- of-care treatment for bladder cancer. However, “we’re hoping neoadjuvant therapy will reduce tumor volume and lead to less invasive surgery and bladder preservation, and also give us good prognostic information when we assess response to chemotherapy,” said Jessica Poirier Duda, PharmD, BCOP, specialty practice pharmacist at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at the Ohio State University Medical Center in Columbus.

She noted that there is a high risk of recurrence in these patients and low overall survival rates. “So there may be a lot of micrometastatic disease that we don’t know when tumor burden is low. And patients may be able to tolerate chemo better when we don’t have complications from surgery or radiation.

“Although radical cystectomy is the gold standard for the treatment of localized muscle-invasive bladder cancer, cisplatin- based neoadjuvant combination chemotherapy should be considered based on performance status,” said Duda. She noted, however, that large, randomized, multicenter trials assessing neoadjuvant chemotherapy are sorely lacking.

Dose-Dense Therapy in Pediatric Ewing Sarcoma
Surgery, if possible, is the current standard of care for local therapy, according to David Henry, MS, BCOP, FASHP, associate professor and interim chair–pharmacy practice at the Uni versity of Kansas School of Pharmacy, in his discussion of the potential benefits and risks of dose-dense therapy for pediatric Ewing sarcoma. Radiation is used commonly if surgery is not possible or for further control after surgery, but treatment can vary according to circumstances.

The question of whether dose density can play a role in this setting has been raised in past studies. One found that increasing doses of doxorubicin was associated with better outcomes, although it compared less intense therapies than are used at present. Another found an increase in 5-year overall survival, from 61% to 72%, after adding ifosfamide and etoposide for half the cycles of vincristine/doxorubicin//cyclophosamide/dactinomycin. There was no improvement found, however, for patients with metastatic disease, which is becoming common in several other studies too.

“There are no data for metastatic disease for dose-dense therapy,” said Henry. “Overall, is there a role for dose intensity? Right now it’s a fairly debatable question.”