Complications of breast and chest wall irradiation for early stage breast cancer


POTENTIAL COMPLICATIONS OF TREATMENT  Potential complications of radiation therapy (RT) for early stage breast cancer are similar in women undergoing BCT or mastectomy; they include arm edema, pneumonitis, rib fractures, brachial plexopathy, secondary malignancies, and long-term cardiac toxicity. Radiation recall dermatitis is discussed in detail elsewhere. (See "Cutaneous complications of chemotherapy", section on Radiation recall and enhancement reactions).

Arm edema  Both the extent of axillary surgery and regional RT after axillary dissection impact upon the risk of arm edema . Because the highest risk follows full axillary radiation after a complete axillary dissection (levels I-III), full axillary RT should be discouraged in this setting. In comparison, limiting axillary RT to the axillary apex following a level I/II axillary node dissection appears to increase the risk of edema only slightly beyond that observed following surgery only. In one series that restricted regional treatment to limited supraclavicular/infraclavicular and apical fields, the rate of arm edema was only 3 percent.

Pneumonitis  The risk of transient lung inflammation following chest wall RT is approximately 5 percent; the risk is greater with increasing lung volume in the tangent fields, treatment to the supraclavicular, axillary apex, and internal mammary regions, the use of concurrent compared to sequential chemotherapy (8.8 versus 1.3 percent in one series), and with either sequential or concurrent use of paclitaxel as a component of adjuvant chemotherapy.

Although some reports have raised concern for an increased risk of radiation fibrosis in women receiving simultaneous tamoxifen and radiation therapy, such an association has not been uniformly observed. This topic is discussed in detail elsewhere. Furthermore, these changes have not been associated with higher rates of symptomatic pneumonitis.

Rib fracture and brachial plexopathy  The risk of treatment-related rib fractures or a brachial plexopathy is extremely low after BCT or postmastectomy RT. In one report, the incidence of a rib fracture was less than 3 percent, and the median time to develop a fracture was about one year. The incidence appears to be higher with RT doses that exceed 50 Gy, and with the use of concomitant chemotherapy, even when the RT dose is <50 Gy.

Permanent brachial plexopathy occurs in less than 1 percent of women receiving 50 Gy in 2 Gy fractions administered to an supraclavicular and axillary apex field. The incidence of plexopathy is significantly higher with an axillary dose greater than 50 Gy, concomitant chemotherapy administration [83], and with daily RT fractions in excess of 2 Gy.

Cardiovascular morbidity  The risk of late cardiovascular events is dependent upon RT technique and dose. The excess mortality observed in early trials of postmastectomy RT was largely a consequence of treatment-related cardiovascular toxicity. More recent studies using modern RT techniques have not documented an increase in cardiovascular mortality in women treated for left-sided (presumably with more myocardium included in the treatment field) compared to right-sided cancers. Thus, careful treatment planning appears to be associated with no significant increase in cardiac toxicity. Nonetheless, prolonged follow-up is needed because of the latency of RT-induced cardiac disease.

Secondary malignancies  Potential treatment-induced secondary malignancies following locoregional radiation include contralateral breast cancers, and sarcomas, lung cancers, and leukemias, all of which are rare. In one series of 1884 patients with clinical stage I/II breast cancer undergoing BCT, 147 (8 percent) developed a second non-breast malignancy by eight years of follow-up. However, when compared to the number of cancers expected in the general population over this same time period extracted from the Surveillance Epidemiology and End-Results (SEER) data base of the National Cancer Institute (n = 128), the relative risk was 1.15 (95 percent confidence interval, 0.97 to 1.35, p = 0.05). Thus, the absolute excess risk associated with radiation therapy was only 19 cases.

  Sarcoma Although women who undergo RT for breast cancer have a slight increase in the risk of in-field sarcomas, the absolute magnitude of the risk for a postirradiation sarcoma is small. In one series of 274,572 cases of primary breast cancer identified from the SEER database, the 15-year cumulative incidence rates for any sarcoma in women who did and did not receive RT were 3.2 and 2.3 per 1000, respectively.

Angiosarcoma, a relatively rare tumor, has occasionally been reported to occur in the breast following irradiation. These tumors usually present as multiple reddish, bluish and purple nodules or areas of skin discoloration. The topic of radiation induced sarcomas after therapy of breast cancer is discussed in detail elsewhere.

  Lung cancer  Modest increases in the absolute rate of lung cancers have been observed following RT  In three separate reports, the relative risk among women treated with RT who survived 10 or more years from diagnosis was between 2.0 and 2.8. The absolute number of women potentially affected with radiation-induced lung cancer is very low; nine cases would be expected in 10,000 women surviving their breast cancers for at least 10 years.

The incidence of lung cancer is related to the volume of lung in the irradiated field. This was illustrated in a study that compared lung cancer rates in 3515 women with early breast cancer treated on two protocols from the National Surgical Adjuvant Breast and Bowel Project (NSABP) of surgery with and without radiation that differed in the extent of irradiation. The B-04 trial randomly assigned women to radical mastectomy, or simple mastectomy with or without radiotherapy to the chest wall, axilla, supraclavicular, and internal mammary areas, while B-06 randomly assigned women to lumpectomy alone, mastectomy alone, or lumpectomy followed by breast irradiation.

With 25-year follow-up of the B-04 trial, the percentage of patients who developed lung cancer after receiving postmastectomy radiation was approximately two-fold higher than with surgery alone (2.1 versus 0.9 percent). In contrast, there was no significant difference in the long-term incidence of lung cancer in women who received postoperative radiotherapy limited to the breast compared to surgery alone in NSABP B-06 (1.7 versus 1.4 percent). These data underscore the importance of treatment planning to limit the extent of normal lung in the radiated field.

Not surprisingly, smoking appears to play a significant role in the development of a second primary lung cancer in irradiated women. Smoking cessation interventions should be encouraged.

  Acute leukemia  In women undergoing chest wall RT, the risk of acute nonlymphocytic leukemias (ANLL) appears to be related to the volume of bone marrow in the field, the total RT dose, and the concomitant use of chemotherapy. The absolute risk is very low, especially with limited bone marrow in the RT field. The following represents the range of findings:

  • In one report of 1253 women undergoing BCT for stage I or II breast cancer, the five- and ten-year cumulative risk of leukemia was 0.08 and 0.8 percent, respectively.
  • In another review, the relative risk of treatment-related ANLL varied from 0.86 to 3.7 following RT compared to 1.3 to 11.5 after chemotherapy alone.
  • A higher relative risk after RT (RR = 10) was noted in NSABP B-04 and B-06 trials; however, there were still only four cases of ANLL compared to the expected 0.39, indicating that ANLL is a rare complication.

  Contralateral breast cancer  Limited data suggest a slight excess of contralateral breast cancers following breast or chest wall RT. The risk may be higher with younger age at treatment. In one report, an increase in relative risk (1.59) was seen only in women under age 45 at the time of treatment. Although the risk of radiation-associated contralateral breast cancer, if it exists, is extremely low, measures to reduce scatter to the opposite breast, such as omission of a medial wedge from tangent fields should be used to reduce the contralateral breast dose.

As noted above, women who have an inherited predisposition to breast cancer (ie, BRCA mutations) have an increased risk of both ipsilateral second primary and contralateral breast cancers compared to the general population.