Trial finds single-dose RT effective in early breast cancer

British researchers believe their work with targeted intraoperative radiotherapy will change the fundamental principles of radiation-based breast cancer treatment. The TARGIT single-dose system delivers a smaller radiation dose without sacrificing the results that can be achieved with whole-breast irradiation.

If widely adopted, this approach could also reduce waiting lists and substantially reduce the cost of radiotherapy, according to the researchers from University College London. But oncologists in the U.S. caution that at least 10 years of long-term follow-up data are needed to determine if the technique lives up to its potential.

In support of single-dose radiotherapy

After breast-conserving surgery, 90% of local recurrences occur very close to the index quadrant, despite the presence of multicentric cancers elsewhere in the breast. The TARGIT-A international multicenter clinical trial was launched in 2000 and enrolled 2,232 patients with invasive ductal carcinoma. The researchers analyzed the results of TARGIT with conventional whole-breast external-beam radiotherapy (EBRT) using local recurrence as the primary outcome measure. The investigators found a therapeutic equivalence between TARGIT and EBRT. At four years, there were six local recurrences in the TARGIT group and five in the EBRT group.

The trial population consisted of 1,113 patients randomized to TARGIT and 1,119 patients to EBRT (see Table 1). Of the patients in the TARGIT arm, 86% received TARGIT only and 14% underwent TARGIT and EBRT. Ninety-two percent of the women in the EBRT group received the assigned treatment.

TABLE 1.

TARGIT-A trial demographics

Mean age: 63 years (82% of pts were less than 70 years old)

Median tumor size: 12 mm

Lymph nodes: 17% positive

The researchers found that the frequency of any complications and major toxicities was similar in the two groups. Wound breakdown or delayed healing also was similar in the two groups. There were 31 cases in the TARGIT group and 21 cases in the EBRT group. However, RTOG grade 3 toxicity was less common in the TARGIT group (6 cases) vs the EBRT group (21 cases).

"It is the sincere hope of the TARGIT group that these results influence a paradigm shift from conventional radiation approaches to single-dose treatment for eligible patients," said Michael Baum, MD, cochair of the TARGIT-A trial and a professor emeritus of surgery at University College London.

The TARGIT-A team noted that in addition to the benefits of completing all the radiotherapy in a single session at the time of surgery, TARGIT almost completely avoids irradiation of the intrathoracic structures such as the heart, lungs, and esophagus (Lancet 376:91-102, 2010; American Society of Clinical Oncology [ASCO] abstract LBA517).

TARGIT technology

"These data change two fundamental principles of breast cancer treatment in selected patients. The first is that TARGIT single-dose treatment can replace whole-breast radiotherapy approaches, which are time-consuming and uncomfortable for the patient. The second is that a much smaller radiation dose can be adequate to achieve similar outcomes, thereby reducing toxicity and eliminating certain side eff ects," said Jayant Vaidya, MD, PhD, a reader in breast surgery and oncology at University College London.

Dr. Vaidya is a coinventor of the TARGIT system along with Dr. Baum and Jeffrey S. Tobias, MD, from the radiation oncology department at University College London.

"It is important to recognize that TARGIT-A compared risk-adjusted radiotherapy with whole-breast-EBRT-for-all," Dr. Vaidya emphasized. "Within the trial, 14% of the patients who received TARGIT also received EBRT. Among those who received TARGIT at the time of the first operation, 21% also received EBRT because prespecified adverse pathology was found postoperatively. Thus, nearly four out of five patients did not need further radiotherapy."

TARGIT uses the Intrabeam radiotherapy system, which employs a mobile radiotherapy platform with a miniature electronic low-energy x-ray source equipped with a 10-cm-long probe. The use of low-energy x-ray radiation eliminates the need for a specialized treatment room, in contrast to other high-energy radiation sources (linear accelerators, high-dose-rate systems, brachytherapy systems).

The Intrabeam system, a proprietary technology of Carl Zeiss Meditec, is set up to be used in the operating room at the time of surgery. The Intrabeam radiation is applied for 20 to 30 minutes, exposing the affected tissue in the tumor bed from inside the tumor cavity.

Professor Baum said this study demonstrates that 25 minutes of radiotherapy in the operating room is equivalent to six weeks of postoperative radiotherapy. His group's study results may well change how women with early invasive breast cancer receive their radiotherapy.

"The technique was developed by my group in London and then taken up by [physicians in] Germany, Australia, Italy, Denmark, Israel, and, more recently, the U.S.," he said (see Related Reading at right). "New sites are rapidly coming online in India, France, Finland, and Thailand. The advantage is that it's all over in one go. Also, we can confirm that the wound cavity can be conformed perfectly to the applicator. It can also be used for very superficial tumors simply by reflecting the skin back from the neck of the applicator. The disadvantage is that it adds about 45 minutes to the procedure. But that doesn't worry the [patient]."

The TARGIT-A team reported that treatment of patients with breast cancer now accounts for about 30% of the workload of radiotherapy departments in some parts of the world and contributes to unacceptable waiting lists in many oncology departments worldwide. Since this one-time single dose of radiation is used in place of multiple weeks of radiotherapy, there is also hope that it could result in a huge cost savings.

U.S. group in TARGIT-A sets sights on multicenter trial

The University of California, San Francisco was one of the institutions that participated in TARGIT-A, enrolling nearly 100 patients in the trial. The UCSF team is now working on a multicenter TARGIT trial in the U.S., said Michael D. Alvarado, MD, who served as UCSF's principal investigator for TARGIT-A.

"What is exciting and new is that the radiation is actually delivered during surgery," he said. "The radiation given in the operating room treats the area more precisely, and the fact that it is immediate may also be beneficial."

"The benefits are not only convenience; we believe it will be less dangerous than irradiating the whole breast because there is less 'scatter' to the lungs and heart, and fewer problems with the breast becoming hard aft er radiation," added Dr. Alvarado, a breast cancer surgeon at the Carol Franc Buck Breast Care Center at the UCSF Helen Diller Family Comprehensive Cancer Center.

Laura Esserman, MD, MBA, served as a member of the international steering committee for TARGIT-A. "The target device is truly an innovation in radiation oncology and helps change our thinking about how to achieve breast conservation," she said.

"We have identified a subset of patients for whom it is safe, and we should ensure that all such patients can access this technology. We will continue to study this device in higher risk patients to see if its role can be expanded," said Dr. Esserman, director of the UCSF Carol Franc Buck Breast Care Center and coleader of the breast oncology program.

Source: UCSF news release, June 7, 2010

TARGIT could result in a savings of approximately $23 million a year alone, they said. However, the group caution that follow-up is essential, and ongoing studies are needed to ascertain the long-term advantages and disadvantages of TARGIT.

Promising short-term results

Oncology News International spoke with radiation oncologists in the U.S., who all agreed that longer term data are needed before TARGIT can be greenlighted in routine practice.

David Mattson, MD, said the findings from this study are encouraging and many centers around the world may quickly adopt this approach and make it available to their patients. However, Dr. Mattson said the follow-up is not long enough in the current study and this approach will need to be assessed in a wider population of breast cancer patients.

"[TARGIT-A] selected patients who were older than 45 years and there were some exclusion criteria," said Dr. Mattson, director of the breast program in radiation medicine at Roswell Park Cancer Institute in Buffalo, N.Y. He added that questions remain about how eff ective this approach may be in women with breast cancer who didn't meet the criteria for this study.

Paul Petruska, MD, director of hematology and oncology at Saint Louis University, commented that follow-up of five to 10 years is really required to know the true value of this approach. "The data at the present time look very good," Dr. Peradiation truska said. "It could replace EBRT. There are some rival methods that are similar and they are also under investigation (see Table 2). We need to wait and see if in 10 years the numbers are the same."

TABLE 2.

Types of accelerated partial-breast irradiation

•Brachytherapy

•3D conformal partial-breast irradiation

•Intraoperative radiation therapy (IORT)