Novel modalities to administer radiation therapy for early stage breast cancer have received increased attention. Partial breast irradiation using brachytherapy delivers radiation to a smaller volume of breast tissue by directing radiation to the tissue adjacent to the excised lesion. Evidence demonstrates that partial breast irradiation results in excellent outcomes with respect to local tumor control, toxicity, and cosmesis at five year follow-up [1–4].
In contrast, a recent SEER database report suggested that PBRT may be inferior to WBRT, with a doubling of recurrence rates in women over 66 years of age . However, this was a retrospective surrogate analysis of insurance data. Moreover, the suitability of patient selection for breast brachytherapy (PBRT) has been called into question [52–54], with one SEER study  showing that 65% of women receiving PBRT fell in the unsuitable cautionary group for PBRT based on the American Society of Radiation Oncology guidelines. This may explain the increased local recurrence reported by Smith et al.,. At this time, definitive conclusions regarding local control and survival outcomes for PBRT must await completion of an ongoing national study comparing PBRT to WBRT [5, 6].
PBRT may offer other advantages for women undergoing adjuvant radiation therapy for breast cancer. Since WBRT irradiates a greater volume of breast and normal tissues than PBRT, it may lead to greater and more prolonged treatment-associated symptoms than PBRT. For some women the longer duration of daily therapy sessions can be physically and emotionally taxing and PBRT may be better tolerated . Our findings demonstrate that women who receive PBRT, delivered for five days with brachytherapy, exhibit a trajectory of decreasing fatigue, compared to women receiving WBRT, who exhibit worsening fatigue after radiation therapy. These results are consistent with a recent retrospective study, which showed that accelerated (3 weeks) partial breast irradiation resulted in lower maximum fatigue during treatment and lower severe fatigue at treatment completion compared to conventional 6-week whole breast irradiation . Treatment modalities with lower associated fatigue are clinically meaningful, as fatigue is one of the most burdensome symptoms experienced by cancer patients . For most individuals receiving radiation therapy, fatigue subsides to pre-treatment levels within 4–8 weeks after treatment completion [56–58]. Yet, for some cancer survivors, fatigue can become a chronic disabling condition, persisting for months or years after successful cancer treatment .
A prior small study evaluated quality of life in women receiving PBRT and showed improvements (change from pre-surgical values) in emotional well being at 1 month post-PBRT, which was followed months later by gains in social/family well-being [43–45]. Yet that study did not compare outcomes of quality of life for women receiving PBRT to that of women receiving WBRT, nor was fatigue evaluated. Our results show baseline levels of quality of life to be good for both groups . However, over time post-radiation quality of life shows an increasing trajectory in quality of life for women receiving PBRT, but a decreasing trajectory of quality of life for women receiving WBRT. Based on established criteria for what is considered a minimally important difference (i.e., >5 point difference for the FACT-G total score), the difference in quality of life between these groups is considered meaningful [60–62].
It is possible that the increasing trajectory in quality of life we observed for women receiving PBRT may be related to lower fatigue, as previous findings confirm that cancer-related fatigue significantly interferes with the course of daily living, diminishing quality of life [10, 63]. For women in the present study, baseline levels of fatigue for both groups of women are within the range of general population norms reported for the FACT-F scale . However, post-radiation we observe a decreasing trajectory of fatigue for women who received PBRT, but an increasing trajectory for women who received WBRT. By 6 weeks post-radiation, the lower fatigue for women in the WBRT is at levels within the range reported for non-anemic cancer patients . Further, the increasing difference in fatigue observed across trajectories can be interpreted as meaningful, as the minimal important difference for the FACT-F scale is established to be in the range of 3–4 points [65, 66]. A shorter more focused course of radiation therapy that results in lower fatigue and higher quality of life offers clear advantage for women who are unable to tolerate either a mastectomy or a longer course of radiation treatment. This is an important consideration for elderly women with breast cancer , as older age was demonstrated to predict higher fatigue during radiation therapy for breast cancer .
The underlying factors contributing to the differences we observed in fatigue for women who received WBRT versus those who received PBRT remain unclear. Psychological factors are known to contribute to variation in radiation-associated fatigue severity and duration [15, 68]. For women in the present study, perceived stress scores are moderately elevated at baseline [23, 48]. By 6-weeks post-radiation, the perceived stress scores return to levels similar to normative levels reported for women without breast cancer . However, we do not observe differences in perceived stress based on type of radiation therapy. Others show that depressive symptoms predict higher fatigue trajectories for women with breast cancer undergoing radiation therapy . Although we did not measure depressive symptoms, it is possible that women receiving WBRT experience more depressive symptoms, increasing risk for higher post-treatment fatigue.
Biological factors may underlie cancer-related fatigue [22, 69, 70], in that circulating proinflammatory cytokines can signal the brain and engender behavioral symptoms like fatigue and depression [71, 72]. Previous reports demonstrate that women with breast cancer exhibit elevated levels and/or production of proinflammatory cytokines [9, 23, 24], with concomitant fatigue and depressive symptoms [9, 70, 73, 74]. Moreover, a quantitative meta-analysis concluded that fatigue is associated with elevations in circulating levels of IL-6 in cancer patients . Others identify inflammatory processes as potential mediators of radiation-induced fatigue in breast and prostate cancer patients . This may result from exposure to radiation, which triggers inflammatory processes that promote tissue repair [75, 76]. WBRT may generate a greater inflammatory response, resulting in more intense and sustained fatigue and lower quality of life.
NK cells conduct immune surveillance against tumors [27, 29, 32] and breast cancer is responsive to the anti-tumor effects of NK cells [27, 30–34]. Studies show that higher NKCA predicts a better prognosis for cancer patients [77–82]. As well, women with breast cancer who report more behavioral symptom distress exhibit lower NKCA [23–25], which may be mediated by elevations in stress hormones [80, 83–85]. Our results did not reveal differences in NKCA based on type of breast radiation therapy. This may be related to the lack of observed differences in perceived stress between the two treatment groups. However, post hoc analysis revealed that the perception of better quality of life predicted higher NKCA, post-treatment, for both groups of women (i.e., WBRT and PBRT). We previously showed that a mindfulness based stress-reduction program for women undergoing breast cancer treatment improved quality of life, as well as reduced cortisol levels and increased NKCA restoration after cancer treatment . It is possible that the perception of better quality of life during cancer treatment, as observed in this study, may reduce endocrine stress signals, resulting higher NKCA [69, 85].