UPDATED November 18, 2013 — The difference in the rates of local recurrence in the 2 TARGIT-A groups was incorrectly identified as nonsignificant; in fact, the difference was statistically significant and the text has been corrected to reflect that.
Single-dose radiotherapy delivered during or soon after breast cancer surgery is a viable alternative to the more time-consuming multiple-fraction whole-breast approaches that are currently widely used, according to 2 new major studies.
However, intraoperative radiotherapy is only a "reliable alternative" in a "carefully selected population at low risk of local recurrence," write David Azria, MD, and Claire Lemanski, MD, in a comment published online November 11 in the Lancet.
The pair, from the Department of Radiation Oncology at the Institut du Cancer Montpellier in France, say that the novel approach is an "attractive option" because it is specifically targeted to the tumor site and has "few side effects."
Intraoperative radiotherapy is delivered in a single dose, eliminating the time and effort of getting to a radiotherapy center for 25 to 33 fractions of whole-breast irradiation. However, it resulted in higher local recurrence rates in the Targeted Intraoperative Radiotherapy Alone (TARGIT-A) trial, published online November 11 in the Lancet, and the Electron Intraoperative Radiotherapy (ELIOT) trial, published online November 11 in the Lancet Oncology.
In each trial, intraoperative radiotherapy was compared with conventional external whole-breast irradiation (EBRT).
With the TARGIT technique, the difference in recurrence was within a prespecified noninferiority boundary but was statistically significant nonetheless. With the ELIOT technique, the difference was also statistically significant, favoring conventional EBRT.
However, the TARGIT technique offered better overall survival than conventional EBRT. In ELIOT, survival was only
The authors of these studies believe that their respective intraoperative radiotherapy techniques should be offered as an option to women undergoing lumpectomy for breast cancer.
Because the respective trials used different types of intraoperative radiotherapy and different designs and had different results, each trial needs to be considered individually, note Drs. Azria and Lemanski.
Better Survival with TARGIT
In the TARGIT-A trial for early breast cancer, an international team of researchers compared 1 intraoperative dose of 20 Gy using a spherical applicator with EBRT delivered according to standard schedules over several weeks (using tangential fields without node irradiation). The randomized study was a noninferiority trial of women undergoing lumpectomy.
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), report the authors, led by Jayant Vaidya, MD, from University College London in the United Kingdom. However, the absolute difference was within the predefined noninferiority margin of 2.5%.
These results were first presented in 2012 at the San Antonio Breast Cancer Symposium, as reported at that time by Medscape Medical News.
Dr. Vaidya and colleagues add more survival data in their Lancet publication, and the results are good news for the intraoperative radiotherapy approach.
Overall, breast cancer mortality was similar between the TARGIT and EBRT groups (2.6% vs 1.9%; P = .56). However, there were significantly fewer non-breast-cancer deaths with TARGIT than with EBRT (1.4% vs 3.5%; P = .0086), which was attributable to fewer deaths from cardiovascular causes and other cancers, the authors report. Overall mortality was 3.9% for TARGIT and 5.3% for EBRT (P = .099).
In the study population, median follow-up was 2 years and 5 months for 3451 patients, 4 years for 2020 patients, and 5 years for 1222 patients.
There was also an advantage in terms of toxicity with TARGIT, the authors note.
Wound-related complications were similar in the 2 groups, but there were significantly fewer grade 3 or 4 radiotherapy-related complications in the 1720 patients treated with TARGIT than in the 1731 treated with EBRT (0.23% vs 0.75%; P = .029).
Dr. Vaidya and colleagues emphasize that their study was not primarily a comparison of TARGIT and EBRT; instead, it was a trial of 2 policies in a "risk-adapted design."
They explain that, initially, TARGIT was delivered concurrently with lumpectomy (n = 2298), but some centers delivered the intraoperative radiotherapy as a second procedure after tumor pathology reports (n = 1153). Thus, there were 2 strata — prepathology and postpathology. If the pathology report suggested adverse histologic features, the patient received whole-breast radiation. About 15% of cases in the postpathology group ended up receiving EBRT, but that did not compromise the trial's statistical validity.
"This trial therefore has a true pragmatic design, reflecting practice in the real world," the authors point out.
The results reported above reflect the combined results from the prepathology and postpathology strata. However, the authors also reported results by individual stratum.
Importantly, they found that in the prepathology stratum, local recurrence was 2.1% with TARGIT and 1.1% with EBRT (P = .31). There was no significant difference between the randomized groups when TARGIT was concurrent with surgery. In other words, when TARGIT was delayed a day or so by a pathology report, it was not as effective. The results show that the method is best when used during surgery.
Local recurrence with single-dose TARGIT is comparable to that seen with EBRT given over several weeks, which raises the question: How does it work?
The authors offer some speculation. "Radiobiological studies suggest that one or a few fractions of larger doses, delivered to a small volume in a shorter overall treatment time, increases the biologically equivalent dose," they write.
They provide a detailed description of how the TARGIT technique, which was pioneered by investigators at University College London, functions in practical terms. An intrabeam device (Carl Zeiss Meditec, Oberkochen, Germany) provides a point source of 50 kV energy x-rays at the center of a spherical applicator. The appropriately sized applicator (1.5 to 5.0 cm diameter) is placed in the tumor bed using a purse-string suture. Radiation is delivered for 20 to 45 minutes to the tumor bed.
The TARGIT technique is "fundamentally different" from the technique used in the ELIOT study, Dr. Vaidya and coauthors explain.
TARGIT delivers radiation from within the "undisturbed tumor bed," they write. With ELIOT, the mammary gland is mobilized, a prepectoral lead shield is inserted, and the edges of the tumor bed are apposed. Radiation (21 Gy) is then delivered from without.
In ELIOT, Italian investigators randomized 1305 patients after lumpectomy to receive either EBRT (50 Gy in 25 fractions followed by a boost of 10 Gy in 5 fractions without node irradiation) or intraoperative radiotherapy with electrons.
The primary outcome was ipsilateral breast tumor recurrence (IBTR).
The 5-year event rate for IBTR was 4.4% (95% confidence interval [CI], 2.7 - 6.1) with ELIOT and 0.4% (95% CI, 0.0 - 1.0) with EBRT. Median follow-up was 5.8 years.
Local recurrence of less than 7.5% in the ELIOT group was deemed by investigators to show efficacy equivalent to that of EBRT.
Thus, even though the rate of local recurrence with ELIOT intraoperative radiotherapy was within the prespecified equivalence margin, it was "significantly worse" than that for EBRT, write the authors, led by Umberto Veronesi, MD, from the European Institute of Oncology in Milan.
Despite the different rates of recurrence, overall survival at 5 years was similar in the ELIOT and EBRT groups (34 vs 31 deaths). There were also no significant differences between the groups with respect to breast-cancer-related deaths.
Dr. Veronesi and colleagues assessed associations between patient characteristics in the ELIOT group and local recurrence to identify which characteristics seem unfavorable for intraoperative radiotherapy alone.
They found that tumors larger than 2 cm, grade 3 tumors, 4 or more positive nodes, and triple-negative tumors were significantly associated with local recurrence. These criteria require further validation, the investigators note.
"Although our results show that 5-year rates of local recurrence were significantly higher in women who received ELIOT, we need to bear in mind that for some women, the benefits of not needing to complete weeks of radiotherapy will outweigh a higher risk of local recurrence," said Dr. Veronesi in a press statement.
The TARGIT-A study was supported by University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre and other sources. The ELIOT study was supported by the Italian Association for Cancer Research and other sources. A number of the TARGIT-A authors report financial relationships with Carl Zeiss, the maker of the radiotherapy technology used in TARGIT. The ELIOT authors have disclosed no relevant financial relationships.
Lancet. Published online November 11, 2013. Comment, TARGIT-A abstract
Lancet Oncol. Published online November 11, 2013. ELIOT abstract
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