Based on a keynote address given by Marie Overgaard, md, at the 1998 American Society for Therapeutic Radiology and Oncology (ASTRO) meeting. Dr. Overgaard is consulting oncologist, Aarhus University Hospital, Denmark, as well as chair of the radiotherapy committee of the Danish Breast Cancer Cooperative Group.
Radiotherapy is currently used as an adjuvant after mastectomy in high-risk patients, after breast-conserving surgery in patients with locally advanced disease or locoregional recurrences, and in palliation. Dr. Overgaard focused her remarks on the most controversial indication; namely, adjuvant locoregional irradiation in early breast cancer, which, in principle, includes radiotherapy after both mastectomy and breast-conserving surgery. The aim of radiotherapy in early breast cancer is to improve both locoregional control and overall survival.
Early Breast Cancer Trialists Meta-Analysis
The impact of radiotherapy on survival was evaluated in a meta-analysis by the Early Breast Cancer Trialists Collaborative Group published in the New England Journal of Medicine in 1995. The results of studies comparing surgery alone vs the same surgery plus radiotherapy indicated no benefit of irradiation at 10 years in terms of sur-vival for either node-negative or node-positive patients. So why should we bother about this topic when the gold standard in evidence-based medicinethe meta-analysishas established that this issue is dead? Dr. Overgaard asked.
A second look at the overview analysis, however, reveals that, although there was no difference in overall survival, there were several important differences in the two treatment groups. First, the addition of radiotherapy significantly reduced locoregional recurrences, with a risk ratio of 0.33. Second, the analysis of cause-specific deaths showed a small, but significant, reduction in breast cancer deaths in irradiated patients, with a risk ratio of 0.94. This was counterbalanced by an excess of nonbreast cancer deaths, mainly of cardiovascular disease, with a risk ratio of 1.24.
Thus, there is a clear general beneficial effect of radiotherapy on local control. However, the potential beneficial effect of radiotherapy on survival needs to be clarified further, Dr. Overgaard said. A number of potential problems in the studies included in the meta-analysis need to be kept in mind. These include the definition of end points and aims of the trials, selection of patients according to prognostic factors, quality of radiotherapy, and interaction with other therapies, such as surgery and adjuvant endocrine therapy and chemotherapy.
Danish Breast Cancer Group Trials
In the first protocols initiated in 1977, the Danish Breast Cancer Group (DBCG) evaluated the effect of adjuvant systemic therapy in high-risk patients. At that time, all high-risk patients received postoperative radiotherapy in addition to total mastectomy and partial axillary dissection. As in many similar trials, the DBCG found a positive effect of adjuvant systemic therapy on survival.
The theory that breast cancer seems to be a systemic disease, as described by Bernard Fischer in 1980, implies that changes in locoregional treatment are unlikely to affect survival. In light of this, the DBCG decided to evaluate the role of postoperative irradiation in high-risk patients who were also receiving adjuvant systemic therapy. Dr. Overgaard focused her discussion on those protocols.
The aim of the DBCG 82B and 82C protocols, she noted, was to evaluate postmastectomy irradiation in patients who were also given adjuvant systemic therapy. Between 1982 and 1989, more than 3,000 patients were enrolled in the two studies. The studies asked: (1) whether postoperative radiotherapy is necessary in high-risk breast cancer patients who also receive adjuvant systemic therapy; and (2) more generally, whether optimal locoregional tumor control influences survival in high-risk breast cancer patients who are also receiving adjuvant systemic therapy. The 82B trial was published in 1997 in the New England Journal of Medicine; the 82C trial has just been accepted for publication.
According to the design of DBCG 82B and 82C, premenopausal patients were randomized, after surgery, to receive either adjuvant systemic chemotherapy with CMF (cyclophosphamide, methotrexate(Drug information on methotrexate), and fluorouracil(Drug information on fluorouracil)) plus radiotherapy or CMF alone. Postmenopausal patients were randomized to tamoxifen(Drug information on tamoxifen) (Nolvadex) plus radiotherapy or tamoxifen alone. Only high-risk patients were included (ie, those with primary tumor size larger than 5 cm and/or positive nodes and/or tumor invasion into skin or deep fascia on pathology).
All of the patients were initially treated with total mastectomy, including clearing of level 1 axillary nodes and part of level 2 nodes. Patients randomized to radiotherapy received irradiation to the chest wall and regional lymph nodes, including the internal mammary chain, to a median absorbed dose of 48 to 50 Gy in 22 to 25 fractions over 5 weeks. The systemic treatment consisted of eight to nine cycles of intravenous CMF every 4 weeks in premenopausal patients, and 1 year of tamoxifen (30 mg/d) in postmenopausal patients. Radiotherapy and CMF were given sequentially, with one cycle of CMF before 5 weeks of radiotherapy; after 1 week, CMF was continued every 4 weeks.
The 82B and 82C trials indicated that postmastectomy irradiation combined with adjuvant systemic therapy in high-risk patients causes a major reduction in locoregional recurrences and significantly improves disease-free survival, as well as overall survival. These effects of radiation therapy on survival are of the same magnitude as those seen after adjuvant systemic therapy.
Other Trials of Radiation Plus Systemic Therapy
The Danish studies are not the only trials that have shown the benefit of postoperative radiotherapy plus adjuvant systemic therapy, Dr. Overgaard pointed out. For example, results of the British Columbia trial, published by Joseph Ragaz et al in the New England Journal of Medicine in October 1997, were similar to those of the Danish trials. The British Columbia trial included high-risk premenopausal patients treated with mastectomy and adjuvant CMF with and without radiotherapy.
A number of other published studies evaluating the effect of radiotherapy in high-risk breast cancer patients treated with adjuvant systemic therapy (with or without radiotherapy) were also included in the Early Breast Cancer Trialists meta-analyses from 1995. Most of these studies are too small to show significant effects on survival. However, the pattern of local recurrence in irradiated vs nonirradiated patients is very similar in all of the studies: a three to sixfold reduction in local recurrences.
From a review of the available studies evaluating the effect of radiotherapy in the presence of adjuvant systemic therapy, Dr. Overgaard concluded that postoperative radiotherapy in addition to adjuvant systemic therapy causes a major reduction in locoregional recurrences in this high-risk group, as well as a significant reduction in breast cancer mortality, which is of clinically relevant magnitude.
Thus far, adjuvant systemic treatment does not sufficiently prevent local recurrences, and such residual, inadequately treated locoregional disease can lead to secondary dissemination and thereby impair survival. Therefore, according to Dr. Overgaard, effective locoregional treatment is necessary to cure patients with breast cancer.
This concept is in agreement with Samuel Hellmanns spectrum theory (1994) that breast cancer is a heterogeneous disease. The spectrum ranges from a disease that remains localized throughout its course to a disease that is systemic when first detected. Thus, there could be situations where metastasis would develop as a consequence of residual, inadequately treated locoregional disease, which is what we have seen, said Dr. Overgaard.
According to Dr. Overgaard, the most important message of the Danish trials is that locoregional tumor control has an impact on survival. The current challenge is to find the right balance of treatment modalities that provides optimal local control.
Morbidity of Radiation Therapy
There are many delicate, critical structures around and behind the breast, and radiation produces important adverse effects in these structures. Some of these effects cause only minor symptomsfor example, telangectasia of the skin and lung fibrosis limited to the apex of the lungwhereas other complications, such as arm edema, impairment of shoulder movement, and brachial plexopathy, can cause serious disability. Ischemic heart disease, another complication of radiation therapy, can even be life-threatening.
Morbidity from radiotherapy is influenced by interactions with chemotherapy and surgery, Dr. Overgaard pointed out. It is also dose- and fractionation-related, as well as volume- and target-related.
In the DBCG 77 trial, patients received concurrent CMF and radiotherapy and were then randomized to receive further CMF or no CMF to study the effect of simultaneous radiotherapy and CMF on late skin fibrosis. For the same total radiation dose, simultaneous CMF and radiotherapy resulted in increased late skin damage. To avoid this problem, patients were given sequential chemotherapy and radiotherapy in the present trial.
Data from the 1977 trial, in which hyperfractionation was used in some radiotherapy departments while others used conventional schedules, also show an interaction of radiation therapy with surgery, Dr. Overgaard said. The frequency of arm edema increased with the number of nodes removed. In addition, hyperfractionation, or two large fractions weekly instead of five standard fractions weekly, greatly increased the risk of arm edema, and, therefore, conventional fractionation schedules were used in the 82 trials. The most important end point, cardiac morbidity, has been evaluated in the 82B and 82C trials, presented at the European Society for Therapeutic Radiology and Oncology (ESTRO) meeting in Edinburgh (1998). No evidence of increased long-term cardiac morbidity or mortality was found in irradiated patients, compared with nonirradiated patients.
The Early Breast Cancer Trialists overview concluded that some of the local therapies for breast cancer had substantially different effects on the rates of local recurrence, such as the reduced recurrence with the addition of radiotherapy to surgery, but that there was no definite difference in overall survival at 10 years, Dr. Overgaard commented. This seems to disagree with the general conclusion of the meta-analysis and the studies I have just presented. Where lies the truth?
In Dr. Overgaards view, a general survival benefit from radiotherapy would not be expected to emerge in an overview of such heterogeneous trials. The survival benefit occurs in only a proportion of those who benefit with regard to local controlnamely, patients who do not yet have disseminated disease. In the vast majority of patients, radiotherapy will only confer a benefit with regard to local control; therefore, it is important to select the relevant group if the objective of radiotherapy is to improve survival. A clinical relevant benefit in survival can be demonstrated in subgroups, including patients with high-risk prognostic features, such as those who have positive lymph nodes and those who also receive adjuvant systemic therapy to overcome disseminated disease.
Although there is evidence of increased long-term cardiac morbidity with radiotherapy, this apparently can be avoided by the use of a proper treatment plan and radiation technique, as shown in the Danish trials.
Optimal locoregional tumor control has an impact on survival in early breast cancer; there is also clear evidence that residual, inadequately treated locoregional disease can result in subsequent dissemination. In addition, adjuvant radiotherapy is an important part of the multidisciplinary treatment of breast cancer. Thus, the indications for radiotherapy are to improve locoregional control in patients who have a high risk of developing locoregional recurrence after surgery, and to improve survival in patients who have a high risk of residual tumor after surgery and do not yet have disseminated disease, or in whom adjuvant systemic therapy can control disseminated disease.
The effort to find an optimal balance among the treatment modalities must be continued, Dr. Overgaard concluded. There are many problems to solve yetfor example, defining the optimal extent of the target of radiotherapy and the optimal timing with respect to systemic treatment. The challenge is to strive for progress in both tumor control and reduced morbidity.