Mounting Evidence for Postmastectomy Locoregional Radiation Therapy

Déjà vu All Over Again? Although a substantial number of women will suffer and die from breast cancer during the upcoming years, we clearly have made stepwise progress in treating patients with this cancer over the last 3 decades. Each of these steps of progress has led to what are glibly designated “paradigm shifts.” Perhaps the most hotly debated of these paradigms is the local vs systemic nature of early-stage disease.[1] The theory that breast cancer progressed logically from breast to surrounding lymph nodes to distant organs, championed by Halsted during the turn of the last century, dominated both thought and therapy for the next 50 to 75 years.[2] First Two Paradigm Shifts The first paradigm shift began in the late 1940s through the early ’80s. During that period, a series of prospective, randomized trials demonstrated that “aggressive” local therapy did not result in superior overall survival when compared to what appeared to be “less aggressive” approaches. These studies compared chest wall radiotherapy after mastectomy to mastectomy alone, radical mastectomy to modified radical mastectomy, and breast-conserving therapy to breast removal. Studies addressing the latter issue included conservative surgery with breast radiation vs mastectomy, and conservative surgery with breast radiation vs conservative surgery alone.[3] Overall survival notwithstanding, a fundamental concept that was established by these trials was that less comprehensive local therapy consistently resulted in higher rates of locoregional recurrence. However, until recently, it was exceedingly difficult to detect survival differences between women who received chest wall radiotherapy and those who did not. The lack of survival benefit from more aggressive local therapy, coupled with the observed survival benefits conferred by adjuvant systemic therapy, led to the so-called systemic paradigm of breast cancer, supplanting the theory of Halsted and his successors.[1,2] By the late 1980s, standard dogma excluded “adjuvant” locoregional radiotherapy after mastectomy for stage I and II patients. Rather, chest wall radiotherapy was felt to provide only “upfront palliation,” which, in the absence of a survival benefit, was considered to be more efficiently provided to patients if and when they subsequently suffered a relapse. The ‘Two Wave’ Paradigm In the late 1970s and early ’80s, several groups of investigators reasoned that reality might fall somewhere between the two paradigms.[4] Stated concisely, they speculated that perhaps breast cancer metastases occur in two “waves”: one prior to detection, stemming from the original primary, and a second arising sometime later from a reservoir of inadequately sterilized locoregional disease. In this case, adjuvant systemic therapy might eradicate the first wave of micrometastases, while locoregional radiotherapy would prevent the second. To test this hypothesis, a series of prospective, randomized trials was begun in the early to mid 1980s in which all patients were given adjuvant systemic therapy and were randomly assigned to receive or not to receive chest wall radiotherapy after mastectomy. The mature results of at least three of these studies have suggested that this “intermediate” paradigm may be more reflective of breast cancer biology than either extreme.[5-7] Indeed, the proportional reductions in subsequent distant recurrence and death among patients who received chest wall radiation therapy in these studies are similar to those ascribed to adjuvant systemic therapy by earlier prospective, randomized trials. As reviewed by Marks et al, the results of the chest wall radiotherapy studies have resurrected a concept that most clinicians felt was resolved, ie, that more aggressive local therapy