'Clash of Titans' About Novel Radiotherapy for Breast Cancer

Nick Mulcahy

July 28, 2015

A war of words appears to be escalating between two camps of radiation oncologists over the results of a major clinical trial of early-stage breast cancer. It has been called a "clash of titans" by some observers.

Each camp insists that they have the best interests of patients in mind, and each has stinging words for their rivals.

The subject of the dispute is a form of radiotherapy for breast cancer that is administered during lumpectomy and only requires a single dose; it has thus been called "one-stop" radiotherapy.

In the TARGIT-A trial, the technique known as targeted intraoperative radiotherapy (TARGIT) was compared with standard fractionated external-beam radiotherapy (EBRT), which is administered over several weeks.

In the noninferiority trial, the 5-year risk for local recurrence in the conserved breast was higher with TARGIT than with EBRT (3.3% vs 1.3%; P = .042). The difference was statistically significant in favor of EBRT, but the absolute difference was within the predefined noninferiority margin of 2.5%. Cosmesis was generally better with the new technology, and serious grade 3 or 4 skin complications were significantly reduced with TARGIT.

Results from the TARGIT-A trial were initially presented at a meeting in 2012, and were then published in the Lancet (2014;383:603-613), as previously reported by Medscape Medical News.

Ever since, the results have led to "vigorous debate" and "polar opposite views," writes Anthony Zietman, MD, editor in chief of the International Journal of Radiation Oncology * Biology * Physics, known as the Red Journal, in an editor's introduction in the August 1 issue. Dr Zietman is also an endowed professor of radiation oncology at Harvard Medical School in Boston.

Because of the convenience of intraoperative radiotherapy, the TARGIT approach represents a potentially radical change in radiation oncology for breast cancer, he suggests.

However, the detractors see the technology as a danger to patients because the risk for local recurrence is higher with TARGIT than with standard radiotherapy.

"Depending on your perspective, intraoperative radiation therapy is thus either a very serious threat or a quantum leap forward," says Dr Zietman.

 
[TARGIT is] either a very serious threat or a quantum leap forward.
 

He explains that, when used in conjunction with lumpectomy, fractionated radiation therapy, delivered daily over several weeks, helped women with breast cancer "move from a dark past of radical mastectomy into the modern era of breast conservation."

But TARGIT-A "suggests that there may be another way to achieve [breast conservation]," writes Dr Zietman, and weeks of radiation might be mostly unneeded in early-stage breast cancer.

Clearly a lot is at stake.

"Many careers have been built around fractionated radiation therapy for breast cancer, and it comprises a substantial proportion of the practice of the average contemporary radiation oncologist," he points out.

The only resolution to the current debate will be more mature data from TARGIT-A trial and other studies, says Dr Zietman.

Other experts agree.

"The follow-up is very short; we need longer-term results," said Bruce Haffty, MD, board chair of the American Society of Radiation Oncology (ASTRO). He was referring to the 5-year primary outcome data on local recurrence from TARGIT-A, and noted that when the results were published, median follow-up was only 29 months.

However, "the randomized data suggest that the short-term outcome is acceptable," he told Medscape Medical News.

 
ASTRO doesn't have a formal position yet.
 

"ASTRO doesn't have a formal position yet on the use of intraoperative radiation," he added.

EBRT to the whole breast is the current standard of care in breast cancer, but partial-breast irradiation is increasingly being used, explained Dr Haffty, who is from the Cancer Institute of New Jersey in New Brunswick.

In 2016, ASTRO will issue a consensus statement on partial-breast irradiation, of which there are now many types, including relatively novel intraoperative radiation approaches, such as TARGIT and electron intraoperative radiotherapy (ELIOT). TARGIT is more widely used because it is "easier to use and adopt" than the "more complex" ELIOT, he said.

While the data mature, the debate about intraoperative radiation, especially TARGIT, continues.

In an editorial published in the February 1 issue of the Red Journal, two critics — David Wazer, MD, from Tufts University in Boston, and Jaroslaw Hepel, MD, from Brown University in Providence, Rhode Island — called TARGIT-A a "flawed study" that "should not define a new standard of care" (Int J Radiat Oncol Biol Phys. 2015; 91:255-257).

Then in the July 1 issue, the TARGIT-A authors, including first author Jayant Vaidya, MBBS, PhD, from University College London in the United Kingdom — said that attitudes about the study results were being guided by "pride, prejudice, and science," with the latter, obviously, being more desirable (Int J Radiat Oncol Biol Phys. 2015;92:491-497).

Now, in the August 1 issue, more voices have joined the debate in the form of multiple letters to the editor, curated by Dr Zietman.

First up are critics Dr Wazer and Dr Hepel, who have nine cosigners on their letter.

After taking a general swipe at their rivals — "Sadly, the TARGIT-A authors continue on a path of obfuscation and distraction" — these critics get down to specifics.

They say the publication of the TARGIT-A local recurrence results were "premature" because there was less than 2.5 years of median follow-up.

The critics then state that the study authors, in an attempt to rationalize the hurry to publish, "incorrectly" claim that breast recurrences peak in the second and third year after treatment, and that EBRT is ineffective in controlling local recurrence after 5 years.

The "overwhelming preponderance of contemporary evidence" indicates that the benefit of EBRT "continues to expand beyond 10 years of follow-up," the critics write.

They also critique the trial's statistical methods, which they say cast doubt that the noninferiority margin of 2.5%.

The TARGIT-A authors respond to the criticism.

"The objections to the trial seem to be theoretical or ad hominem attacks," the study authors argue. The critics, the study authors say, are a "vociferous minority."

The TARGIT-A authors note that the study "questioned the prevailing dogma" about radiation therapy in this setting.

"We find a striking absence of true scientific discourse in much of the [critics'] content," the authors write. "Instead it seems we have a clash of ideologies."

Patients and clinicians can decide whether or not they find the TARGIT technology and currently compiled data attractive, the TARGIT-A authors conclude. "The widespread adoption of TARGIT intraoperative radiation therapy in more than 260 major breast cancer centers worldwide speaks for itself," they write.

In all, 10 letters have been published in the Red Journal, and they are all "passionately and articulately expressed," according to Dr Zietman. Together, the letters add up to an exchange of opinion the likes of which has not been seen in radiation oncology in recent memory, he says.

In one letter, four clinicians from Israel, led by Orit Kaidar-Person, MD, from Rambam Health Care in Haifa, say that "only time will resolve the clash of titans."

Dr Zietman has disclosed no relevant financial relationships. A number of the TARGIT-A authors report financial relationships with Carl Zeiss, the maker of the radiotherapy technology used in TARGIT.

Int J Radiat Oncol Biol Phys. 2015;92:951-952. Editor's introduction

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