Landmark Partial Breast Irradiation Trial Needs "Unsuitable" Patients

Nick Mulcahy

November 11, 2009

November 11, 2009 (Chicago Illinois) — Clinicians may have gotten the "wrong message" about patients categorized as "unsuitable" for accelerated partial breast irradiation (APBI) in a recent consensus statement issued by the American Society for Radiation Oncology (ASTRO), according to a presenter here at the organization's annual meeting.

Dr. Frank Vicini

"There's been some decrease in the enrollment of our phase 3 trial since the guidelines came out," Frank Vicini, MD, told Medscape Oncology, referring to the landmark Radiation Therapy Oncology Group (RTOG) 0413 and the National Surgical Adjuvant Breast Project (NSABP) B-39 trial, which is collectively comparing APBI with whole-breast irradiation in a randomized design.

Dr. Vicini suspects that confusion about the concept of unsuitable patients is partially to blame.

ASTRO issued a consensus statement in October, as reported by Medscape Oncology, to help clinicians determine the "use of APBI outside the framework of a clinical trial."

In other words, there are no unsuitable patients for the APBI clinical trial. The term only applies to certain patients outside of a clinical trial and in clinics (off protocol).

The patients described as unsuitable for partial breast irradiation are not inappropriate for this phase 3 trial.

"The patients described as unsuitable for partial breast irradiation are not inappropriate for this phase 3 trial," Dr. Vicini emphasized.

Dr. Vicini, who is from William Beaumont Hospital in Royal Oak, Michigan, explained that the consensus statement grouped women with breast cancer into 3 categories: suitable, cautionary, and unsuitable.

The description of unsuitable was based on the fact that there are "very limited" data about the use of APBI in certain women, said Dr. Vicini.

The authors of the consensus statement, one of whom was Dr. Vicini, said that the definition of unsuitable was subject to change on the basis of more authoritative data, including NSABP B-39/RTOG 0413.

According to the ASTRO consensus statement, unsuitable patients are those who meet any of the following criteria: less than 50 years of age, use of neoadjuvant chemotherapy, tumor size of more than 3 cm, positive margins, any positive lymph nodes, no axillary surgery, extensive lymphovascular space invasion, multicentricity, ductal carcinoma in situ (DCIS) of more than 3 cm, and the presence of a BRCA1 or 2 mutation. "If any of these factors are present, the Task Force recommends against the use of APBI outside of a prospective clinical trial," the authors write.

"The idea behind the ASTRO consensus statement was to prevent treatment of women with partial breast irradiation where there were no data to support its use," Derek McHaffie, MD, from the University of Wisconsin in Madison, told Medscape Oncology.

"However, if the ongoing phase 3 trial fails to mature and fails to enroll a variety of patient types, we may never have all of the answers about who is appropriate for partial breast irradiation," said Dr. McHaffie, who made a presentation on his institution's experience with APBI at the meeting.

Unsuitable Patients Have Comparable 5-Year Local Recurrence Rate

At ASTRO, Dr. Vicini presented updated 5-year data from the 1440-patient registry trial of MammoSite, one of the APBI technologies. Dr. Vicini performed a special analysis on the data to make a point about unsuitable patients.

In the registry trial, 176 patients fit the description of unsuitable, including 130 who were younger than 50 years of age at diagnosis. At 5 years, the in-breast tumor recurrence (IBTR) for unsuitable patients was 5.28%; for the rest of the invasive cases in the registry, it was 3.91%. The difference was not statistically significant (= .2362)

"This supports enrollment of these high-risk unsuitable patients in NSABP B-39/RTOG 0413," Dr. Vicini told the audience at ASTRO.

However, Deborah Fowble, MD, from the University of California San Francisco, who moderated the session at which Dr. Vicini and Dr. McHaffie made their presentations, questioned the appropriateness of using APBI in women younger than 50 years.

Dr. Vicini, who calls Dr. Fowble a "good friend," said that her concerns might be "invalid" because failure rates are comparable with APBI and whole-breast irradiation in young women.

Let's put these women in the phase 3 trial so we can find out the answers.

"Let's put these women in the phase 3 trial so we can find out the answers," said Dr. Vicini, echoing the sentiments expressed by Dr. McHaffie.

At this point, the NSABP B-39/RTOG 0413 trial is only enrolling patients younger than 50 years, those of any age with estrogen-receptor-negative tumors, and those of any age with pN1 tumors. "These patients overlap with the unsuitable group," said Dr. Vicini. "Clinicians may have stopped referring these patients based on this term," he reiterated.

Update Recurrence Data From MammoSite Trial

While oncologists await the results of NSABP B-39/RTOG 0413, they need guidance about how to use APBI in the clinic, said Dr. Vicini; hence, the importance of the consensus statement.

Everyone is holding their breath on partial breast irradiation.

"Everyone is holding their breath on partial-breast irradiation," incoming ASTRO president Anthony Zietman, MD, told Medscape Oncology, referring to the landmark phase 3 trial underway. "The consensus statement is a placeholder," said Dr. Zietman, who is from Harvard Medical School in Boston, Massachusetts.

"The unique thing about the ASTRO consensus statement is that the authors were able to settle on a group of patients that clinicians should be comfortable with," Dr. Vicini explained, referring to the suitable patients.

The ASTRO criteria for suitable patients include age of 60 years or older, a tumor size of 2 cm or less, tumor stage T1, negative margins of at least 2 mm, pathologically negative nodes, positive estrogen-receptor status, an absence of lymphovascular space invasion, and no multicentricity. Patients with DCIS are excluded.

"That is an extraordinary consensus because there are minimal phase 3 data on partial breast irradiation, he said.

Aside from the consensus statement, clinicians can also look for direction from the largest clinical trial of APBI, the MammoSite Breast Brachytherapy Registry Trial, said Dr. Vicini. The registry trial was originally undertaken by the manufacturer of the MammoSite device but, since 2003, has been run by the American Society of Breast Surgeons.

The MammoSite registry trial gives us an early window.

"The MammoSite registry trial gives us an early window through which to see what the risk factors for local recurrence are," said Dr. Vicini, who is coprincipal investigator of the trial and has no ties to the manufacturer. "We now know the importance of local recurrence," noted Dr. Vicini, referring to the finding that local recurrence is associated with decreased overall survival in invasive breast cancer (Lancet. 2005;366:2087-2106).

In the trial, the 5-year rates of IBTR (3.8%) with MammoSite, which uses a balloon catheter to deliver brachytherapy, are comparable to rates achieved with similar follow-up with the more established form of APBI, interstitial brachytherapy, said Dr. Vicini in his presentation of the new data.

The great majority of the cases in the registry are invasive, with only a minority of DCIS, explained Dr. Vicini. Overall, only estrogen-receptor status had a statistically significant association with IBTR (P = .0022); an age of either less than or more than 50 years was not significant, he said.

The researchers have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 51st Annual Meeting: Abstract 159. Presented November 4, 2009.

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