The median follow-up for the surviving patients was 64 months (range, 7–240 months). For the 256 patients, there were 56 locoregional recurrences, 152 distant failures, and 159 deaths. Of the 256 patients, 192 (75%) successfully completed treatment as intended with a combination of doxorubicin-based chemotherapy, mastectomy, and postmastectomy radiation. A total of 64 patients (25%) were not able to complete the intended course of treatment because of poor disease response. Of these 64 patients, 21 underwent preoperative radiation followed by surgery because of poor response to preoperative chemotherapy; 21 underwent definitive radiation alone because of disease extents; and 22 experienced local disease recurrence after mastectomy but before postmastectomy radiation. These 64 patients more commonly had supraclavicular lymph node involvement at presentation as well as positive surgical margins after mastectomy than the group of 192 patients who were treated with adjuvant postmastectomy radiation as planned.
Locoregional control and survival
shows the actuarial rates of LRC, DMFS, and OS for the 256 patients as a whole and a comparison of the 192 patients who completed the planned course of treatment and the 64 who did not. The actuarial 5-year LRC, DMFS, and OS rates for the entire population were 76%, 40%, and 44%, respectively. Not surprisingly, patients who were able to complete multimodality therapy as intended had significantly better rates of 5-year LRC (84% vs. 51%), DMFS (47% vs. 20%), and OS (51% vs. 24%) than those who could not complete the treatment as planned (p <0.0001 for all comparisons). A multivariate analysis for the entire group confirmed that inability to complete treatment as plan was independently associated with a statistically inferior outcome for all three endpoints.
Fig. 1 (Top left) Overall survival (OS), locoregional control (LRC), and distant metastasis–free survival (DMFS) in all patients in the series (n = 256). (Top right) OS in patients able to complete combined-modality therapy as intended (group 1, n = (more ...)
Patient, tumor, and treatment characteristics
details the patient, tumor, and treatment characteristics for the entire study population and the 192 patients who were able to complete the planned course of treatment. In all, 95% of patients received neoadjuvant chemotherapy. Of the patients who received neoadjuvant chemotherapy, 21% achieved a clinical CR, 59% a clinical PR, and 20% less than a PR.
Patient, tumor, and treatment characteristics for entire patient population and for subgroup of patients who completed the planned course of treatment*
For the 192 patients who went on to have a mastectomy and postmastectomy radiation, at the time of surgical resection, negative margins were achieved in 70% of patients, whereas in the remaining 30% the margins were either positive or of unknown status. At mastectomy, 47% of the patients had lymph node involvement ranging from no nodes to three, whereas 53% had more advanced disease with involvement of four or more nodes. The median number of recovered axillary lymph nodes was 13. A total of 77 patients (40%) received a taxane as a component of their chemotherapy.
With respect to the course of postmastectomy radiation therapy, 80% of patients were treated with an accelerated hyperfractionated schedule that involved twice-daily 1.5-Gy fractions. The 20% of patients who were treated with once-daily 2-Gy fractions either were treated during the early years of this series or were unable to receive twice-daily treatments, mainly for logistical reasons that made it difficult to come to the hospital twice a day. The standard total dose before 1986 was 60 Gy, whereas the standard dose from 1986 to the end of the study period was 66 Gy. We compared the locoregional treatment outcomes according to total dose (≤60 Gy vs. >60 Gy). Of the patients, 79 (41%) received ≤60 Gy, and their median total dose was 60 Gy (range, 43.5–60 Gy). The 113 (59%) patients in the higher-dose group received a median dose of 66 Gy (range, 61–72 Gy). In the 60-Gy treatment group, 58% were treated with twice-daily treatment and 42% with once-daily treatment. In the 66-Gy group, 96% were treated with twice-daily treatment.
Locoregional control for patients who completed the planned treatment
In an effort to determine variables that were associated with locoregional recurrence after postmastectomy radiation, we evaluated the relationship between patient, tumor, and treatment-related factors and LRC in the 192 patients who completed the planned course of treatment. Data from this analysis are shown in . The variable with the strongest association with LRC was clinical response to neoadjuvant chemotherapy. The 5-year LRC rate was 95% for the 42 patients with a clinical CR, 86% for the 111 patients experiencing a PR, and 51% in the 30 patients with less than a PR (p <0.0001). Clinical response to neoadjuvant chemotherapy was also the strongest predictor of both OS and DMFS. Of patients who had a clinical CR, 70% were free of metastatic disease and 73% were alive at 5 years, whereas of those who had a PR, 42% were metastasis free and 51% were alive at 5 years. Patients with less than a PR had a particularly poor prognosis; all 30 of these patients experienced distant recurrence by 5 years, and only 12% survived 5 years (p < 0.0001 for all comparisons).
Univariate analysis of variables associated with locoregional control for patients who were able to complete the planned course of treatment
Other factors significantly associated with LRC included surgical margin status, number of pathologically positive lymph nodes, and whether a patient received taxane chemotherapy. Patients with negative margins had an LRC rate of 91% at 5 years, whereas those with positive or unknown margin status had an LRC rate of 68% (p = 0.0005). Patients with lymph node involvement of no to three nodes had a better LRC rate than patients with four or more involved lymph nodes (94% vs. 74%, respectively; p = 0.006). Patients who received a taxane in addition to doxorubicin-based chemotherapy had a better 5-year LRC rate than patients who did not receive a taxane (92% vs. 79%, respectively; p = 0.04).
Of the 192 patients, 184 were able to complete the planned course of treatment received neoadjuvant chemotherapy, mastectomy, and postmastectomy radiation. Among these 184 patients, 29 had no residual invasive disease within the breast or lymph nodes (pathological complete response [pCR]); 64 had residual disease in the breast but no positive lymph nodes (n = 13) or one to three positive lymph nodes after chemotherapy (n = 51); and 91 had four or more positive lymph nodes after chemotherapy. The respective 5-year rates of LRC were 96% in the pCR group vs. 83% in the non-pCR group with positive lymph nodes ranging from none to three and 76% in the group with four or more positive lymph nodes (p = 0.019).
Adjuvant chemotherapy was used in 152 of 184 patients treated with neoadjuvant chemotherapy and appeared to have no impact on LRC (85% yes vs. 84% no, p = 0.975).
Multivariate analysis, which incorporated all variables associated with LRC, found two factors that remained independently significant: namely, clinical response to chemotherapy and surgical margin status.
Effect of radiation fractionation schedule and total dose
In the group of 192 patients who completed the course of planned treatment, the actuarial 5-year LRC rates for patients treated with once-daily or twice-daily fractionation did not differ significantly (81% vs. 84%, respectively; p = 0.98); but the small number of patients treated with once-daily fractionation limits the significance of this comparison. Similarly there was no statistical difference in LRC according the mean total radiation dose. At 5 years, the LRC rate of the patients who received a mean total dose of 60 Gy was 78%, whereas that for the patients that received a mean total dose of 66 Gy was 88% (p = 0.17).
Although dose did not appear to have an independent significant effect on LRC rates, further analyses were performed to determine if higher dosages may benefit particular subsets. shows the effect of radiation dose according to response to neoadjuvant chemotherapy. For patients who experienced a clinical CR or PR, the dose of postmastectomy radiation did not have a statistically significant impact on LRC; 86% of patients treated to 60 Gy maintained LRC at 5 years, whereas 91% of patients treated to 66 Gy maintained LRC over the same interval (p = 0.72). For patients whose disease did not have a PR to chemotherapy, a higher dose was associated with a significant benefit in LRC. Of these patients, 70% who received 66 Gy had LRC at 5 years, whereas 32% of those who received only 60 Gy had LRC at 5 years (p = 0.04).
Fig. 2 (Top) Locoregional control (LRC) as a function of response to neoadjuvant chemotherapy. (Bottom left) LRC in patients who experienced at least a PR to chemotherapy as a function of radiation dose (n = 94 for dose 66 Gy, n = 59 for 60 Gy). (Bottom right) (more ...)
shows the effect of margin status on LRC and stratifies the patients by this parameter to assess the impact of radiation dose in these subsets. Patients with negative surgical margins did not appear to benefit from higher radiation doses; the 5-year LRC rate was 93% in patients treated to 60 Gy and 90% in patients treated to 66 Gy (p = 0.41). For patients whose surgical margins were close, positive, or unknown, however, the 5-year LRC rates were 60% in patients treated to 60 Gy and 83% in patients treated to 66 Gy (p = 0.12).
Fig. 3 (Top) Locoregional control (LRC) as a function of surgical margin status. (Bottom left) LRC in patients with negative surgical margins as a function of radiation dose (n = 87 for dose 66 Gy, n = 46 for 60 Gy). (Bottom right) LRC in patients with positive (more ...)
shows that LRC was marginally better in the group of women >45 years of age (86% 5-year LRC rate) than in those ≤45 years (79%), although this difference was not statistically significant. Nonetheless, in assessing the effect of dose in these two groups, the patients ≤45 years of age did appear to have a significant improvement in 5-year LRC with a higher dose of postmastectomy radiation (86% LRC in the 66-Gy group vs. 65% LRC in the 60-Gy group; p = 0.01).
Fig. 4 (Top) Locoregional control (LRC) as a function of age (≤45 years vs. >45 years). (Bottom left) LRC in patients aged ≤45 years as a function of radiation dose (n = 45 for dose 66 Gy, n = 25 for 60 Gy). (Bottom right) LRC in patients (more ...)
For each curve shown in to , we also analyzed the effect of once-daily vs. twice-daily fractionation for the 60-Gy dose level and found no clinically apparent or statistical difference between these two fractional schemes. There were too few patients treated once daily to 66 Gy to allow any such comparison within the 66-Gy dose level. We also analyzed the effect of dose on patients with four or more positive lymph nodes after chemotherapy and did not find a statistically significant difference in outcome in LRC in this subgroup.
Actuarial Grade 3 to 4 complication rates in patients treated to a lower radiation dose of 60 Gy (n = 79) vs. a higher dose of 66 Gy (n = 113).
details the types and incidences of late Grade 3 to 4 complications in patients treated to 60 or 66 Gy. Of the 79 patients treated to a median dose of 60 Gy, 12 developed at least one Grade 3 to 4 late complication, whereas of the 113 patients treated to a median dose of 66 Gy, 28 had at least one such complication. The most common Grade 3 to 4 late side effects were severe chest wall fibrosis (n = 10), symptomatic lymphedema (n = 12), and severe telangiectasia (n = 9). The major difference between the two dose groups was in the development of symptomatic lymphedema (n = 2 in the 60-Gy group, n = 10 in the 66-Gy group). Moreover, 2 patients who received the higher dose developed brachial plexopathy. Both of these patients had supraclavicular lymphadenopathy at diagnosis. Brachial plexopathy was not observed in the lower-dose group. shows the actuarial risk of developing a Grade 3 to 4 late complication as a function of radiation dose (29% in the 66-Gy group vs. 15% in the 60-Gy group, p = 0.08). The effect of fractionation schedule (once-daily vs. twice-daily treatment) within the 66-Gy dose arm could not be evaluated because 96% of the patients treated to 66 Gy received twice-daily fractionation.
Grade 3 to 4 late complications observed for all patients completing combined-modality therapy as planned*