BARCELONA (EGMN) – Although the risk of locoregional recurrence is undoubtedly reduced by the use of radiotherapy, uncertainty remains over the risk of second malignancies resulting from such treatment, according to two studies presented at the biennial meeting of the European Society for Therapeutic Radiation and Oncology.

New long-term data from the Stockholm mastectomy trial confirm that a major reduction in locoregional recurrence can be achieved with adjuvant radiotherapy of the breast, with no increased risk of contralateral or second malignancies.

Data from the European ALLEGRO project show, however, that the 20-year risk of second primary malignancies is higher in irradiated vs. nonirradiated women, with sites near the delivery of radiation being the most affected.

The Stockholm Mastectomy Trial

Radiotherapy is associated with a threefold decrease in the risk of locoregional recurrence in breast cancer, “but there is concern about the potential increase in non–breast cancer mortality,” said Dr. Rodrigo Arriagada, professor of oncology-pathology at the Karolinska Institute and University Hospital, Stockholm.

Dr. Arriagada presented findings from a median of 32 years’ follow-up of the Stockholm mastectomy trial in which 960 women with breast cancer were treated with pre- or postoperative radiotherapy or with modified radical mastectomy alone. Patients in the trial were recruited in 1971-1976, and those who received radiotherapy were treated with doses of 45 Gy given in 25 fractions over a 5-week period (J. Clin. Oncol. 1995;13:2869-78). The Swedish Tumor Registry reported second malignancies systematically.

When women in the radiotherapy arms were compared with those who were given no radiotherapy, the hazard ratio for overall survival was 0.90 (P = .16) and the HR for event-free survival was 0.79 (P less than .001). Locoregional recurrence was significantly reduced (HR, 0.29; P less than .001), with a nonsignificant trend for fewer distant metastases (HR, 0.87; P = .18) with radiotherapy vs. no radiotherapy.

In node-positive patients given radiotherapy, the hazard ratios for locoregional recurrence (0.24; P less than .0001) and distant metastases (0.65; P = .009) were significant. The HR for overall death in node-positive patients was 0.82 (P = .17).

Considering all patients, the risks of contralateral breast cancer and second malignancies were not significantly different between the patients who had received pre- or postoperative radiotherapy and those who had mastectomy alone.

“Adjuvant radiotherapy significantly decreases the risk of locoregional recurrences,” Dr. Arriagada said. “In high-risk patients with positive nodes, it may also decrease the incidence of distant metastases, and then have a positive impact on overall survival.”

Although later side effects, such as cardiovascular complications, may compromise the potential overall survival benefit, Dr. Arriagada concluded that long-term follow-up of oncology trials is essential in order to obtain complete information on likely complications of therapy.

The ALLEGRO Project

“The ALLEGRO project aims to address many of the early and late health risks to normal health tissue from the use of existing and emerging techniques in radiation therapy,” Trine Grantzau, a Ph.D. candidate from Aarhus (Denmark) University Hospital, said at the meeting. She noted that ALLEGRO involves collaboration by 13 institutions in eight European countries.

Linking data supplied by the Danish Breast Cancer Cooperative Group to the Danish Cancer Registry, the investigators were able to identify 47,518 women who were treated for early breast cancer in 1982-2007 and for whom follow-up data at 1 year after diagnosis were available. Of these, 24,316 had received postoperative radiotherapy whereas the remaining 23,202 had not.

In all, 2,958 second primary malignancies occurred, of which 1,187 were potentially related to the use of postoperative radiotherapy. Second malignancies occurred in a variety of locations, but mostly affected the respiratory, digestive, or genitourinary organs.

“All of these sites are within or close to the treatment field,” Ms. Grantzau said. “We have selected these sites out of an a priori assumption that these sites have received [radiotherapy] doses that could be potentially carcinogenic.”

Standardized incidence ratios (SIRs) were calculated for second primary cancers occurring from the 1-year follow-up to 20 or more years post diagnosis. The SIR “estimates the occurrence of cancer in a cohort relative to what would be expected in the general population – in this case, the general female Danish population,” the investigator explained.

For all 47,518 women who were identified as 1-year cancer survivors, SIRs at 1-4, 10-14, and 20 or more years after a breast cancer diagnosis were 1.0, 1.3, and 1.3, respectively. The respective SIRs for these time points for the nonirradiated women were 1.0, 1.2, and 1.2, and for the irradiated women were 1.0, 1.5, and 1.8. The difference in SIRs at 20 or more years following diagnosis between irradiated and nonirradiated women did not reach statistical significance (P = .08).

However, when SIRs for potentially radiotherapy-induced vs. nonpotentially radiotherapy-induced sites were compared, significant differences for irradiated vs. nonirradiated women were observed at 10-14 years (1.6 vs. 1.2; P = .03) and 20 or more years (2.6 vs. 0.9; P = .001).

SIRs for various tumor sites were also compared, showing that at 20 or more years after breast cancer diagnosis, irradiated women had a higher SIR ratio for second lung, bronchus, and tracheal malignancies than did the nonirradiated women, at 4.3 vs. 0.7 (P = .0001). Higher SIRs were seen for esophageal and colorectal cancers as well, but the differences did not reach statistical significance.

“There is an increased risk of developing potentially induced cancer, and the risk increases over time since treatment,” Ms. Grantzau said. The ALLEGRO project team will now use a dose-planning system to identify the radiation levels associated with the increased risk.

ALLEGRO is funded under the EURATOM Work Program. Dr. Arriagada and Ms. Grantzau reported no conflicts of interest.

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