Breast-conserving therapy may well be the best-studied therapy in all of medicine, with data available from seven mature prospective randomized trials that compared outcomes with the "gold standard" of ablative mastectomy, as well as data from specific programs across the country and globe, reflecting a broad range of clinical and technical skills and philosophic and technical variations on the theme of breast-conserving therapy. However, relatively little has been published on the late effects of this therapy. Frassica et al have done an excellent job of producing a descriptive catalog of the majority of potential late effects in patients who survive breast-conserving therapy, complete with suggestions regarding management.
If we consider the problem globally, there are three types of late effects that clinicians involved in the posttherapy care of these patients need to know about: those that cause posttherapy symptoms, those that mimic disease recurrence, and, finally, disease recurrence itself.
As the authors noted, a significant proportion of women who have undergone breast-conserving therapy will have residual symptoms long after the acute effects of radiation have subsided. The four most common symptoms are tenderness and/or edema of the breast and soft tissue, edema of the hand and arm, pain and dysfunction of the arm and shoulder, and posttherapy depression. In addition to the less common musculoskeletal effects of rib fracture and periostitis noted by Frassica et al, we have frequently observed tenderness and swelling in the costochondral junction of the anterior rib cage consistent with arthritis and, in rare instances, a chronic and generalized pain syndrome akin to sympathetic reflex dystrophy or fibromyalgia that appears to develop after the onset of shoulder pain and dysfunction.
In most reports based on chart reviews, such symptoms are documented in less than 10% of patients, but in specific patient surveys and focused examinations, approximately 40% of survivors of breast-conserving therapy develop chronic symptoms. Failure to report symptoms may be related to the fear that these symptoms herald a recurrence of disease or the assumption that any intervention might by unsuccessful or too costly.
The general lack of awareness of the magnitude of low-grade chronic symptoms after breast-conserving therapy has retarded the development of effective prevention and intervention strategies. In our institution, once the magnitude of the problem was identified, a more focused evaluation program was developed that led to earlier identification of chronic pain and dysfunction and more aggressive interventions.
A subculture of specialists has developed techniques that have resulted in improvement in almost all patients with chronic symptoms, including complete resolution of detectable arm edema in up to one-third and measurable improvement in most of the rest. These include the use of lymphedema massage, decompression devices, passive and active muscle stretching, and range-of-motion and strengthening exercises. Along with the mechanical efforts to break up adhesions, stretch muscles, and increase lymphatic drainage, the use of vitamin E and pentoxifylline has been associated anecdotally with significant improvement in fibrosis, a decrease in arm edema, and an increase in range of shoulder motion.
Patients have also benefited from education regarding the nature of the problems, risk factors that may trigger or exacerbate symptoms (eg, air travel, superficial skin abrasion, and infection), and signs and symptoms that require immediate medical attention, such as cellulitis. Not only have survivors of breast-conserving therapy benefited from a conscious focus on the identification and aggressive managment of posttherapy late effects, but awareness of these effects has increased among the various therapeutic disciplines involved, resulting in a willingness to change patterns of care. A notable example is the rapid acceptance of lymphoscintigraphy-guided sentinel node biopsy techniques to identify nodenegative patients in whom axillary dissection could be avoided. The availability of information on late effects also contributes to the validity of informed consent.
Processes That Mimic Recurrence
The authors have identified several processes that mimic recurrence, including mammographic changes, fat necrosis, and persistent or intermittent skin inflammation. The posttherapy mammogram frequently demonstrates significant architectural distortion. Over time, these changes stabilize or resolve. Dystrophic calcifications may develop. We have learned from substantial experience with mammography to expect posttherapy changes to require up to 2 years for maximum resolution or stabilization. A posttherapy mammogram performed less than 6 months after the completion of treatment is usually not helpful; frequently, it causes patients great discomfort, and, occasionally, it appears to precipitate fat necrosis.
Fat necrosis most commonly manifests within the first year after treatment as a 1- to 2-mm-sized nodule palpated in the base of a tumor bed whose edges have not been approximated after lumpectomy or as a larger marble-sized mass in the approximated edges of the tumor bed. Mammographic evaluation usually is negative or consistent with an "oil cyst." It is probable that hypoxia, related to surgically compromised vascularity and dose-related radiation effects (ie, a 20% to 25% higher dose in the tumor bed), contributes to the development of fat necrosis. In contrast to fat necrosis, recurrence in the tumor bed area within the first year is rare after breast-conserving therapy, particularly when surgical margins are adequate. An unnecessary biopsy will further compromise the vascular supply, creating more hypoxia and further confusing evaluation of the tumor bed.
In a low-risk setting (ie, negative margins, adequate boost to well identified tumor bed, minimal or no ductal carcinoma in situ [DCIS]), close surveillance at 2- to 3-month intervals is an acceptable alternative to immediate biopsy. Frequently, the lesion will show measurable regression over a 2- to 3-month interval, permitting avoidance of further tissue injury from biopsy. During this interval, it is important to consider interventions that may enhance oxygenation of the tumor bed such as smoking cessation, use of vitamin E and pentoxifylline, gentle massage, and physical therapy.
As the authors point out, the etiology of intermittent inflammatory changes in the skin of the treated breast remains obscure-only rarely can a specific diagnosis of cellulitis or abscess caused by a specific pathogen be made. An intermittent inflammatory change in the breast skin usually occurs in patients who undergo extensive axillary dissection, suggesting breast skin edema as a contributing etiologic factor. Inflammatory breast cancer recurrence in the skin usually occurs after high-grade carcinoma with extensive lymphovascular space invasion and/or nodal metastases. Pruritus is more likely to be associated with inflammatory breast cancer than with intermittent posttherapy inflammatory skin changes. Response to antibiotics tends to be slow and partial. In contrast, inflammatory change in an edematous arm requires expeditious intervention with intravenous antibiotics, as cellulitis may spread rapidly.
Recurrence and Other Ipsilateral Malignant Events
The authors note that several reports have documented excellent rates of disease-free and overall survival following salvage surgery for recurrence after breast-conserving therapy. Different prognostic factors have been identified, including histology (DCIS vs invasive disease) and disease- free interval, but the most consistent and important factor is the extent of disease at the time the recurrence is diagnosed. Patients with tumors less than 2 cm at diagnosis of recurrence do well, with expected survivals similar to those achieved with initial treatment.
In all probability, part of the reason for the excellent outcome with salvage mastectomy in this setting is that these patients are at low risk for spread to regional nodes or distant sites. Typically, they are not considered candidates for further radiation (eg, to the regional nodes). Therefore, if regional nodes are at risk due to the extent of tumor at the time of recurrence, one mainstay of treatment is generally not utilized. In addition, the best chemotherapy options may have been exhausted. As extent of disease is the most important prognostic factor, it is incumbent upon the following physician to diagnose the recurrence at the earliest possible stage.
A rare event after breast-conserving therapy that the authors do not mention is angiosarcoma of the breast skin. Although the incidence of this lesion is low, the popularity of breast-conserving therapy is such that many clinicians involved in the management of breast cancer will encounter at least one case of breast angiosarcoma during their careers. The lesion is asymptomatic, and the signs are subtle-rust brown, red, purple, or bluish discolored skin splotches reminiscent of benign hemangiomas or traumatic ecchymoses, sometimes presenting with an indolent history of waxing and waning prior to explosive growth. Suspicious lesions need close surveillance with biopsy as soon as a diagnosis of traumatic skin ecchymosis is ruled out. Occasional treatment successes have been reported with combinations of aggressive radiation therapy and surgery.
Finally, it is important to recognize that although less information is available on the late effects of mastectomy, this does not necessarily mean that mastectomy is associated with fewer late effects than breast-conserving therapy. One of the main reasons for the difference is that closer surveillance is indicated after breast-conserving therapy than after mastectomy because of the higher probability of salvage in the event of a recurrence.
Financial Disclosure: The authors has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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