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Pulsed Reduced Dose Rate for Reirradiation of Recurrent Breast Cancer
Practical Radiation Oncology (2019) xx, e1-e10
www.practicalradonc.org
Basic Original Report
Pulsed Reduced Dose Rate for Reirradiation of Recurrent Breast Cancer Adam R. Burr, MD, PhD H. Ian Robins, MD, PhD R. Adam Bayliss, PhD and Steven P. Howard, MD, PhD* Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Carbone Cancer Center, Madison, Wisconsin Received 6 March 2019; revised 15 August 2019; accepted 6 September 2019
Abstract Purpose: Locoregionally recurrent breast cancer within a previously irradiated field requires weighing the benefits of reirradiation against the increased rates of toxicity. Here we evaluate the outcomes of patients treated with pulsed reduced dose rate (PRDR) radiation therapy with concurrent low-dose capecitabine as a method to increase the therapeutic ratio of re-treatment. Methods and Materials: Patients treated from November 2000 to June 1, 2018 with PRDR radiation therapy at University of Wisconsin were identified. Patients were re-treated to a median dose of 54 Gy (range, 37.5-66 Gy) using PRDR radiation therapy, delivering radiation at an apparent dose rate of 6.67 cGy/min to allow for increased sublethal damage repair of normal tissues. The median cumulative dose was 109.8 Gy. Twenty-two patients were treated with concurrent capecitabine, most frequently at 500 mg twice per day. The KaplaneMeier method was used for survival analysis, and Cox regression analysis was used for univariate and multivariate analysis. Results: Forty-three patients were identified who underwent reirradiation for locoregionally recurrent invasive breast cancer, with a median follow-up of 20.5 months. Twenty-four patients had gross disease. Nineteen patients had simultaneous metastatic disease. The complete response rate was 83.3% in treated patients with gross disease. Locoregional recurrenceefree survival was 81.3% and 73.8% for all patients at 1 and 2 years, respectively. Overall survival for patients with localized disease was 95.7% at 1 year and 91.1% at 2 years. The rate of acute grade 3 radiation dermatitis was 25.6% with no other acute grade 3 toxicities. Grade 3 late toxicity occurred in 18.6% of patients. Conclusions: PRDR radiation therapy with capecitabine was a well-tolerated and effective method for treating patients with recurrent breast cancer. Prospective studies are necessary to compare side effects and efficacy with conventional dose rate reirradiation and to evaluate the potential role for capecitabine in the recurrent setting. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.
Sources of support: This work had no specific funding. Disclosures: none. * Corresponding author: Steven P. Howard, MD, PhD; E-mail: [email protected] https://doi.org/10.1016/j.prro.2019.09.004 1879-8500/Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.
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A.R. Burr et al
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Introduction
Methods and Materials
Locoregional recurrence of breast cancer within a prior radiation therapy treatment field occurs at a rate of 5% to 15%.1-3 Given the prevalence of breast cancer, this is a challenging situation that will be encountered by the majority of practitioners. In the case of recurrence within the intact breast, this can often be managed with mastectomy alone without the need for reirradiation. However, a subset of cases will have unresectable recurrences, inflammatory recurrences, multiple positive nodes, or positive margins where radiation may be beneficial. Previous studies have shown that in the absence of radiation, recurrence risk after resection of a chest wall recurrence approaches 50% to 70%.4,5 However, given the increased risks of chest wall reirradiation and fibrosis associated with reirradiation, the use of radiation in this context remains controversial. Prior studies evaluating the use of reirradiation after chest wall recurrences have often focused on hyperthermia or superficial brachytherapy as potential treatments to limit the long-term side effects of radiation while maintaining efficacy.6-13 However, hyperthermia is a specialized technique that is difficult to standardize and not universally available. Superficial brachytherapy is similarly specialized and is generally not appropriate for axillary or supraclavicular recurrences. The feasibility of pulsed reduced dose rate (PRDR) radiation therapy as a technique for radiation therapy has been previously demonstrated in several systems.14-19 This technique is believed to limit normal tissue toxicity through improved sublethal damage repair at low dose rates and decreased TGF-b release compared with conventional dose rate radiation therapy.14,15 PRDR radiation therapy may also have therapeutic advantages in terms of tumor control owing to the phenomenon of low-dose hypersensitivity, which has been demonstrated in several model systems.16-19 Another potential advantage of this method is that it can be delivered at any radiation therapy center without the need for specialized techniques such as hyperthermia or brachytherapy. An additional advantage over superficial hyperthermia and brachytherapy techniques is the ability to treat deep-seated recurrences. In brief, we deliver 0.2 Gy pulses every 3 minutes to achieve an effective dose rate of 0.067 Gy/min, using a simple timer to control the delivery of the dose. We have frequently combined this with low-dose capecitabine, a convenient oral radiosensitizing chemotherapy, in an attempt to improve the efficacy of reirradiation. Here, we present our experience with PRDR radiation therapy with concurrent capecitabine as a method for the treatment of recurrent breast cancer.
Patient selection and characteristics All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study did not involve animals. Informed consent was obtained from all individual participants included in the study. A total of 43 patients were included in this study and received reirradiation to an area of locoregional recurrence of breast cancer. Forty-two patients had primary breast histology, and 1 was treated for chest wall angiosarcoma. Seventeen patients were identified from a previously published manuscript,20 and their clinical data were updated here. An additional 24 patients who had been treated at the University of Wisconsin between July 30, 2008, and June 1, 2018, were identified through billing codes and the Aria software package (Varian, Palo Alto, CA). Two additional patients were seen in consultation and follow-up at the University of Wisconsin but were treated at the Beloit Cancer Center which was formerly a satellite facility of University of Wisconsin. Patients who were candidates for reirradiation had completed their prior course of radiation at least 6 months before reirradiation. Patients with localized disease were treated for the following indications: uresectable gross disease, microscopic positive margins, lymph node involvement, or inflammatory recurrence. Patients with metastatic disease were treated to the areas of locoregional recurrence if systemic disease burden was well controlled at the time and the disease was found to be progressing locoregionally. In these cases, the prevention of locoregional progression and associated morbidity was thought to outweigh the risks. Patient characterization at the time of initial diagnosis is included in Table 1. Nineteen patients underwent mastectomy at the time of initial diagnosis. Of the 24 patients who underwent breast-conserving surgery at the time of diagnosis, none underwent reirradiation to the intact breast. All underwent either subsequent mastectomy or radiation to the supraclavicular and axillary region alone. Thirty-four patients underwent initial axillary dissection, with 31 having initial nodal involvement. Breast tangents alone were delivered to 24 patients, and 15 underwent comprehensive irradiation at the time of initial diagnosis. Four patients subsequently received nodal irradiation after breast tangents owing to axillary or supraclavicular recurrence before PRDR therapy. One patient received mantle irradiation as treatment for Hodgkin lymphoma. The median total initial radiation dose was 59.4 Gy.
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Summary of patient characteristics
Patient characteristics, initial surgery, and initial radiation
Nodal status Yes No Axillary dissection At time of breast surgery Delayed dissection No Mastectomy At time of diagnosis Delayed mastectomy No Initial radiation Median dose (range), Gy Breast tangents alone Comprehensive nodal irradiation Metachronous nodal irradiation Mantle
All Patients
No concurrent chemotherapy
Concurrent chemotherapy
31 12
14 6
17 6
29 1 13
13 1 6
16 0 7
19 13 11
5 8 7
14 5 4
P value 1
.55
.06
59.4 (48.6-181.8) 15 21 6 1
Characterization of disease status at the time of recurrence is included in Table 2. Positron emission tomography/computed tomography (CT) restaging was performed for 72% of patients before reirradiation, with CT of the chest, abdomen, and pelvis performed for the remainder. Fourteen patients were re-treated for isolated chest wall recurrences, 14 patients were re-treated for isolated nodal recurrences, and 15 patients were re-treated for multisubsite recurrences. A total of 24 patients were treated for gross disease, 14 patients were treated for microscopically positive margins, and 5 patients were treated with adjuvant therapy. Indications for adjuvant treatment included inflammatory recurrence (2 patients) and extensive nodal involvement (3 patients). Ten patients had additional locoregional recurrences before PRDR radiation. After completion of therapy, the complete response rate was defined by clinical examination in all cases, with the addition of imaging in 70% of cases. Local recurrence was defined as recurrence within the treatment field. Locoregional recurrence was defined as recurrence on the chest wall, axilla, supraclavicular, or internal mammary region. Progression occurred in 3 patients adjacent to the field overlying the humerus, overlying the scapula, and on the anterior abdominal wall. This was considered a distant progression because it was outside of a reasonable radiation field. Progression-free survival was defined, consistent with previous consensus, as freedom from distant progression or death. Assessment of overall survival was augmented using Social Security death searches for patients who were lost to follow-up. Toxicity was scored by Common Terminology Criteria for Adverse Events version 5 for both early and late effects of radiation therapy, except for rib fracture, which was scored in a
59.4 (50-107.8) 7 9 4 0
59.4 (45-181.8) 8 12 2 1
.58
binary manner. Toxicities were only scored if they were new or worsened after radiation therapy. Acute toxicity was specified as toxicity that occurred within 90 days after radiation therapy; chronic toxicity occurred thereafter. Median follow-up was calculated from the initial day of PRDR until the date of last follow-up (Table 2). The median follow-up for all patients was 20.5 months (range, 0.5-147.0 months).
Radiation therapy Field and dose Twenty-two patients were treated with reirradiation with curative intent. Nineteen patients were treated with palliative intent because of metastatic disease at the time of treatment of local disease. Two additional patients were treated with palliative intent, which was indicated at the time of consultation, because of gross disease involvement of brachial plexus. The reirradiation field was confined to a single site in 28 cases, and comprehensive 3- or 4-field radiation was delivered in 15 cases (Table 2). Comprehensive irradiation was defined as irradiation of the chest wall, the axillary nodal region, and the supraclavicular region. The entire region (ie, chest wall, axillary, and supraclavicular) was included in the planning target volume (PTV), with the regions defined similarly to the Radiation Therapy Oncology Group contouring atlas. If gross disease was present, a generous expansion of 1 to 1.5 cm was included, and the PTV was expanded accordingly. Only fields that were previously irradiated were treated with PRDR radiation. Thus, if a woman had received whole-breast radiation with tangents previously and had a chest wall recurrence, only the chest wall would be treated
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A.R. Burr et al Summary of recurrence at re-treatment characteristics
Patient no. Median age (range), y Median follow-up from PRDR, mo Median time to reirradiation, mo Site of recurrence Isolated chest wall Isolated axillary Isolated SCV Isolated IM Multisite Disease burden Gross Microscopic Adjuvant >1 local relapse Yes No Metastases at time of recurrence Yes No Median reirradiation dose (range), Gy Median cumulative dose (range), Gy Median tumor volume (range), cm3 Median volume V95% (range), cm3 Reirradiation site Chest wall only Axillary only SCV only IM only Axillary and SCV Chest wall and axilla Comprehensive
All patients
No concurrent chemotherapy
Concurrent chemotherapy
43 56 (34-80) 20.5 (0.5-147.0) 36.7 (7.9-269.0)
20 63 (45-77) 29.4 (0.5-147.0) 45.2 (14.0-265.0)
23 49 (34-80) 18.2 (1.3-50.4) 29.3 (7.7-269.0)
P value
.37 .43 .43
14 6 6 2 15
5 5 3 0 7
9 1 3 2 8
.22
24 14 5
10 5 5
14 9 0
.04
10 33
7 17
3 16
.29
19 24 54 (30-70) 110 (75-235.8) 42.2 (1-497) 1137 (51-3098)
7 13 54 (30-66) 112 (75-157.8) 21 (4.8-295) 1207.5 (126-3082)
12 11 54 (37.5-70) 110.5 (75-235.8) 46.1 (1-497) 1137 (51-3098)
.27
9 6 3 1 6 2 16
3 3 0 0 5 1 8
.52 .55 .46 .42 .28
6 3 3 1 1 1 8
Abbreviations: IM Z internal mammary; PRDR Z pulsed reduced-dose rate; SCV Z supraclavicular.
with PRDR. The axillary or supraclavicular fields would then be treated with a standard dose rate. The median volume receiving 50% of the radiation dose was 2053 cm3, whereas 1099 cm3 received 95% of the prescription dose. The median point maximum was 115% of prescription due in part to planning constraints of PRDR and to the use of electrons in 7 cases. The prescription re-treatment dose varied from 30 to 70 Gy with a median dose of 54 Gy. The median cumulative dose delivered was 109.6 Gy. Four patients were treated with electrons (9-15 MeV), 35 with photons, 4 with mixed electrons and photons. Two patients were treated with a standard dose rate. PRDR technique As technology has evolved, PRDR delivery has also changed, though the dose rate has remained 0.067 Gy/ min.20-22 All patients underwent CT simulation in a wing board. A standard 3- or 4-field postmastectomy, monoisocentric, 3-dimensional (3D) conformal radiation
therapy technique was used for the majority of patients in this study. The targets were contoured as noted earlier, and the fields were designed to encompass the entire PTV target with a 7-to-10-mm margin to block edge. Five millimeters of bolus was used when treating the chest wall. Four patients were treated with electrons only, 35 patients underwent 3D conformal techniques, and 4 patients were treated with static intensity modulated radiation therapy (IMRT; Varian, True Beam, Palo Alto, CA). The specifics of these techniques are discussed in the following. The simplest cases included in this study were those treated with electrons only to chest wall recurrences, for which the total number of calculated monitor units was divided into segments of 20 cGy and the corresponding segment was delivered every 3 minutes. The 20 cGy “pulse” was delivered at a dose rate of 100 MU/min, which was the lowest dose rate available on Varian EX and Trilogy accelerators. For all cases, regardless of technique,
Practical Radiation Oncology: --- 2019
a digital timer was started at the beginning of each segment, with the following segment started when the timer read 3 minutes. Patients were treated with 0.5 cm of bolus or wet gauze. The 3D conformal technique was used for the vast majority of cases on this study. The advantage of 3D conformal radiation therapy was that in a 3- or 4-field plan, treatment could alternate between the chest wall and axillary/ supraclavicular fields, treating each every 3 minutes and dramatically decreasing treatment times. Generally, field-in-field radiation therapy was not used, so the total number of monitor units per field could be divided by 10 and delivered in 20-cGy segments every 3 minutes, as noted. Physical wedges were used for the majority of patients treated with 3D conformal radiation therapy. Continuous dose rate with volumetric modulated arc therapy was attempted for low-dose-rate treatments at our institution using the advanced treatment modes on the Varian TrueBeam, which allowed continuous delivery of as low as 5 MU/min. Ultimately, it was found that an excess number of faults was occurring, which lengthened treatment time. As a result, static IMRT has since been adopted for all future PRDR plans that use photons. The general method is described in detail by Witt et al.22 Briefly, the challenge with IMRT delivery of PRDR is the variation in dose rate inherent to target and at-risk structures. We have chosen to use the method of Ma et al to limit the average target dose rate to 0.067 Gy/min with a maximum of 0.133 Gy/min.23 Using this technique, we calculate a meter rate and compare the maximum meter rates to choose the lowest meter rate per field. Typically, 7 beams are used per field, with a minimum of 6 MU per segment and a minimum segment size of 6 cm2. We have not routinely used dose constraints, but since implementing IMRT, we have constrained the brachial plexus to less than 105% of the prescription dose.
Chemotherapy Concurrent chemotherapy was administered to 23 patients, and 20 patients received no concurrent chemotherapy. The group that received chemotherapy was more likely to have had a mastectomy at the time of initial diagnosis (P Z .02). Twenty-two patients were treated with concurrent daily capecitabine. Initially, this was dosed at 500 mg in the morning and 1000 mg in the evening (5 patients). We currently treat with 500 mg twice daily to limit short-term toxicity (13 patients). Two patients had unknown capecitabine dosing, and 2 received 650 mg twice daily. One patient was treated with liposomal doxorubicin 40 mg/m2 administered every 2 weeks.
Statistics Statistical analysis was performed using SPSS (IBM, Armonk, NY). The KaplaneMeier method was used to
Summary of patient characteristics
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evaluate local recurrence, locoregional recurrence, progression-free survival, and overall survival. Fisher’s exact test and Pearson’s c2 test were used to compare patients who received concurrent chemotherapy with those who did not.
Results Disease control Among patients with gross disease, the in-field complete response rate was 83.3%. The overall local control rate for all patients in this study was 88.7%, 73.8%, and 71.4% at 1, 2, and 5 years, respectively, after completion of therapy (Fig 1). The locoregional control rate was 81.3%, 73.8%, 60.4% at 1, 2, and 5 years, respectively (Fig 1). Among patients with gross disease, the rate of local control was 78.1%, 57.0%, and 57.0% and locoregional control was 64.8%, 55.5%, and 44.4% at 1, 2, and 5 years, respectively (Fig 1). In patients with microscopic disease, 2 of 12 patients had a locoregional failure with a 1-year locoregional control of 90.9%. Patients with localized disease at the time of reirradiation had overall survival rates of 95.7% and 91.1% at 1 and 2 years, respectively (Fig 1). For patients with localized disease, progression-free survival rates were 82.5% at 1 year and 73.1% at 2 years (Fig 1). Patients with metastatic disease had overall survival rates of 47.4% at 1 year and 17.8% at 2 years (Fig 1). Patients with metastatic disease had progression-free survival rates of 22.2% at 1 year and 16.7% at 2 years (Fig 1). As expected, the progressionfree survival difference was statistically significant between patients with local and metastatic disease.
Univariate and multivariate analysis In an attempt to determine variables associated with treatment outcomes, Cox regression analysis was performed (Table 3). On univariate analysis, a disease-free interval of less than 30 months (median) and the presence of metastatic disease were associated with increased locoregional recurrence and worse overall survival. A Karnofsky performance status score of 80 or less, a reirradiation dose <50 Gy, capecitabine use, and presence of gross disease were correlated with decreased overall survival but not locoregional recurrence. Interestingly, estrogen receptor status, isolated chest wall recurrence, multisite recurrence, and multiple prior recurrences were not correlated with outcome in this study. On multivariable analysis, disease-free interval and metastatic disease were correlated with decreased locoregional control. Disease-free interval, metastatic disease, and a Karnofsky Performance Status score of 80 were correlated with decreased overall survival.
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A.R. Burr et al
0.6 0.4 All patients
0.2 0
Proportion free of recurrence
B
12
24 36 48 months Locoregional recurrence free survival
0
C
24
36 months
48
60
0 12
24 months
36
48
60
Locoregional recurrence free survival 0.8 0.6 0.4
Adjuvant Microscopic Gross
0.2 0 0
12
24 36 months
48
60
Overall survival 1
Localized Metastatic
0.8
0.2
F
Locoregional recurrence free survival 1
Adjuvant Microscopic Gross
0.4
1
All patients
12
0.6
E
0.6
0
0.8
0
0.8
0.2
1
60
1
0.4
Local recurrence free survival
Proportion free of recurrence
0.8
0
Proportion free of recurrence
D
Local Recurrence Free Survival 1
Proportion free of recurrence
Proportion free of recurrence
A
Proportion surviving
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0.6 0.4 0.2
0.8 0.6 0.4
Localized Metastatic
0.2 0
0 0
12
24
36
48
60
0
months
12
24 months
36
48
60
Figure 1 Local control for (A) all patients and (D) treated patients with gross, microscopic, or adjuvant disease. Locoregional control for (B) all patients and (E) treated patients with gross, microscopic, and adjuvant disease. (C) Locoregional control and (F) overall survival for treated patients with localized and metastatic disease.
Toxicity Overall, reirradiation with PRDR radiation therapy was well tolerated, with no grade 4 or 5 toxicities. Acute and Table 3
chronic toxicities are summariezed in Table 4. Acute grade 2 dermatitis occurred in 20 patients (46.5%), whereas grade 3 dermatitis occurred in 11 patients (25.6%). This was equal between patients who received
Univariate and multivariate analysis of variables associated with locoregional recurrence and overall survival
Univariate analysis Disease free interval >30 mo Metastatic disease Local vs comprehensive XRT Reirradiation dose <50 Gy Complete response KPS 80 Capecitabine Gross vs microscopic or adjuvant ER-negative Isolated CW Multiple subsite recurrence Multiple prior recurrences Multivariate Disease-free interval Metastatic disease KPS 80 Reirradiation dose <50
LRR HR
P value
95% CI
OS HR
P value
95% CI
7.14 6.59 0.71 1.82 0.35 1.98 1.72 3.54 2.29 1.08 0.70 0.69
.01 .003 .59 .58 .08 .32 .39 .06 .20 .91 .60 .58
(1.52-33.44) (1.86-23.36) (0.21-2.46) (3.66-31.21) (0.11-1.15) (0.52-7.54) (0.50-5.89) (0.97-12.98) (0.60-8.78) (0.28-4.17) (0.19-2.64) (0.19-2.57)
3.67 4.49 0.73 10.69 1.76 2.83 2.47 3.22 1.67 1.12 1.85 0.93
.003 .00006 .45 .00002 .121 .02 .03 .005 .22 .78 .14 .87
(1.56-8.64) (2.18-10.57) (0.32-1.66) (3.66-31.21) (0.86-3.62) (1.21-6.61) (1.10-5.55) (1.43-7.22) (0.73-3.80) (0.51-2.46) (0.82-4.14) (0.41-2.13)
12.01 12.17 -
.004 .002 -
2.22-65.0 2.60-57.0 -
4.90 7.42 4.01 7.48
.001 .0003 .01 .002
(1.85-12.98) (2.51-21.87) (1.35-12.98) (2.51-21.87)
Abbreviations: CI Z confidence interval; CW Z chest wall; ER Z estrogen receptor; HR Z hazard ratio; KPS Z Karnofsky performance status; LRR Z locoregional recurrence; OS Z overall survival; XRT Z radiation therapy.
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concurrent chemotherapy and those who did not. Among patients treated to the supraclavicular region, 6 of 12 (50%) receiving capecitabine developed grade 1 esophagitis, although no esophagitis was noted among the 13 patients who did not receive capecitabine. Chronic toxicity did not appear to be increased by concurrent chemotherapy. Five patients (12.8%) required hyperbaric oxygen or wound vac placement to heal. Grade 3 lymphedema occurred in 1 patient, with a total of 6 patients developing new grade 1 or 2 lymphedema after treatment. Chronic fibrosis was the most common side effect, occurring in 8 patients (20.5%). Three rib fractures occurred among 38 patients receiving over 100 Gy in cumulative dose to the ribs. Grade 3 fibrosis occurred in 2 patients, grade 2 fibrosis occurred in 3 patients, and grade 1 fibrosis occurred in 3 patients. The total rate of chronic grade 3 toxicity was 16.3%. There was no difference in frequency of grade 3 side effects between patients treated with capecitabine and those who were not. There was a single case of brachial plexopathy in a patient who received axillary and supraclavicular reirradiation for a gross recurrence 12 years before the complication. Her main symptom is mild weakness; she does not have pain or sensory changes. Magnetic resonance imaging of the brachial plexus showed matting and enhancing of the nerves with loss of fat planes. The cumulative radiation dose was 50.4 Gy initially followed 4 years later by 54 Gy without concurrent capcitabine. A total of 33 patients with a median follow-up of 18.6 months received reirradiation to the brachial plexus with a median dose of 110.8 Gy with no additional cases of brachial plexopathy.
Discussion The current study demonstrates the safety and efficacy of PRDR radiation therapy in combination with capecitabine as a method for re-treatment of locoregional breast cancer. The local and locoregional control rates from this study are comparable to those in prior studies. Interestingly, locoregional control was decreased in patients with metastatic disease at the time of diagnosis. Even if 2 patients treated to doses <50 Gy are excluded, the decreased locoregional control remains significant in these patients. There was an increased rate of patients with gross disease in the group treated for metastatic disease (P Z .01). Additionally, when present, the median amount of gross disease was greater at 46 mL versus 21 mL, though this did not reach statistical significance (P Z .47). Neither comprehensive radiation fields nor concurrent chemotherapy was used more frequently in localized versus metastatic disease. Thus, although the difference in control may be due in part to differences in disease burden, caution should be exercised when treating
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Summary of patient characteristics Table 4
Summary of acute and chronic toxicity
Acute toxicity
Acute dermatitis Grade 1 Grade 2 Grade 3 Acute esophagitis Grade 1 Chronic toxicity Chronic lymphedema Grade 1 Grade 2 Grade 3 Chronic fibrosis Grade 1 Grade 2 Grade 3 Necrosis Grade 1 Grade 2 Grade 3 Brachial plexopathy Grade 1
Concurrent P All No chemotherapy value patients concurrent chemotherapy .96 11 20 11
5 10 5
6 10 6
6
0
6 .5
5 1 1
3 0 1
2 1 0 .34
5 3 2
2 3 1
3 0 1
0 0 5
0 0 4
0 0 1
.19
.36 1
1
0
patients without significant symptoms because metastatic patients appear to have less durable locoregional control. In this study, the complete response rate of 83.3% was higher than that observed in the majority of prior studies (Table 5). This rate of complete response with the moderate, median dose of 54 Gy supports the concept of low-dose hypersensitivity. Despite the improvement in complete response rates, 5-year local control and locoregional control were comparable to those in prior studies. Thus, it appears that in several patients, microscopic disease persisted through chemoradiation therapy and regrew at a later date. Several possibilities exist to combat this problem, including increasing radiation dose, potentially through a concomitant boost to gross disease or increasing capecitabine dose. Additional adjuvant systemic therapy strategies could also potentially improve long-term rates of disease control. It remains an open question whether concurrent chemotherapy with capecitabine significantly improves outcomes within this population. There did not appear to be an adverse quantitative feature that was substantially worse in the capecitabine group to explain the worse outcomes. Importantly, although there was an increase in esophagitis rates with concurrent capecitabine, no increase was observed in long-term toxicity. Ultimately,
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Table 5
Review of reirradiation literature Patient no.
Treatment modality and median dose
Range of years
Local recurrence free survival, % (y)
Locoregional recurrenceefree survival, y
Complete response rate, %
Wahl, 200813
81
1993-2005
53 (1) with gross disease, 100 without
NR
57 (67 with hyperthermia and 35 without)
Linthorst, 20158
1996-2011
53 40 39 8 78
Oldenborg, 201511
248 with gross disease 198 patients with microscopic disease or adjuvant 414
External beam radiation with chemotherapy (54%) and hyperthermia (54%), 48 Gy 32 Gy in biweekly 4-Gy fractions with weekly hyperthermia 32 Gy in biweekly 4-Gy fractions with weekly hyperthermia
Auoragh, 20166
18
Muller, 201110
42
Vernon, 199612
306
Harms, 20007
58
Merino, 201524
47
Linthorst, 20139
4.9
1
N/A
11.9
1982-2005
25 (3)
58
24
2004-2011
56 (5)
75
17
1993-2003
62 (5)
NR
19
1988-1991
25 (3) with RT alone versus 45 with RT and hyperthermia* 89 (1) gross 81 (2) gross 75 (3) gross 67 (1) 50 (2)
59 combined (41 with RT alone)
NR
93.3
60.3 (majority g3 telangiectasias)
1993-1999
2008-2013
Abbreviations: CW Z chest wall; NR Z not reported; PDR Z pulsed dose rate; RT Z radiation therapy. * From graph.
14.9
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32 Gy in biweekly 4 Gy fractions with weekly hyperthermia 56 Gy with superficial brachytherapy, 5/23 treatments with concurrent chemotherapy 60 Gy external beam with hyperthermia in 29 Results of 5 randomized trials comparing to RT alone versus RT and hyperthermia Two fractions of 20 Gy using PDR brachytherapy EBRT to mean of cumulative dose of 99.8 Gy to breast and CW
1993-2010
(1) (3) (5) (3) (5)
Late grade 3 toxicity, %
A.R. Burr et al
Study
Practical Radiation Oncology: --- 2019
randomized data are needed to support the use of concurrent chemotherapy; however, until that time, these data provide an estimation of the risk of the addition of capecitabine to chest wall irradiation. At our institution, our practice has evolved to currently offer concurrent chemotherapy to the vast majority of patients with microscopic or gross disease and good performance status. An even more central question is the patients for whom reirradiation is indicated. Certainly, in patients with localized, gross residual disease, radiation appears to allow a chance at cure. Thirty-four percent of patients in this study remained disease free at 5 years after radiation for localized, gross disease. This likely underestimates the true rate of disease control, considering many patients treated in the past several years remain disease free with limited followup. Additionally, we treated 15 metastatic patients with gross, locoregional disease with palliative intent to prevent the significant morbidity and pain associated with locoregional progression. A more challenging clinical judgment must be made in terms of treating patients with microscopic disease or treating in an adjuvant fashion after negative margin resection. Prior studies showed local recurrence rates of 50% to 70% in patients after the excision of chest wall recurrences.4,5 Linthorst et al demonstrated 78% locoregional control at 5 years in patients treated with reirradiation and hyperthermia after complete resection or resection with positive margins, suggesting some benefit to radiation after resection. One would expect this benefit to be greatest in patients with positive margins, for whom the 50% to 70% recurrence rates may be accurate. Indeed, the recently completed Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer trial mandated radiation for patients with positive margin status.25 Local or locoregional failure occurred first in 16 of 158 patients on this trial. Thus, in patients with negative margins, a 50% to 70% recurrence rate likely overestimates the true rate of recurrence in a modern setting. We suggest treating these patients only for high-risk features such as inflammatory recurrence, supraclavicular recurrence, extensive extracapsular extension, or >4 lymph nodes involved. Further work will be especially valuable in assessing subgroups without gross residual disease, for whom radiation can be omitted. After the decision is made to treat with radiation therapy, the radiation field must be defined. Although not associated with increased risk of locoregional recurrence on univariate or multivariate analysis, 3 of 28 patients treated with radiation to a subsite had their first site of locoregional recurrence occur within a standard comprehensive 3-field radiation plan. Thus, comprehensive radiation would have had benefit for a subset of patients and should be considered for those treated curatively. We did not have any instances of failure in internal mammary lymph nodes after reirradiation, and we standardly omit treatment of these lymph nodes unless they are clinically involved.
Summary of patient characteristics
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The potential benefit of reirradiation must be weighed against the risk. The rate of acute grade 3 toxicity in this study was 25.6%. In the palliative context, this rate of toxicity, which incurs significant pain, must be weighed against potential palliative benefit. The grade 3 late toxicity rate was 20.3%, which is similar to 4 prior studies6,10,11,26 but substantially greater than several other studies.8,9,13,26 Interestingly, the rate of late grade 3 toxicity varied from 1% to 24% across 3 studies treating with 32 Gy in 4 Gy biweekly fractions with hyperthermia, demonstrating a challenge in reporting retrospective toxicity data. Smoking and diabetes were not statistically associated with increased rates of toxicity in our study, though we do counsel patients with these comorbidities that they are theoretically at increased risk of complication. No variables were associated with increased rates of toxicity in this study, and larger studies will likely be needed to better identify variables associated with substantial risk of toxicity. The weaknesses of this study include its relatively small sample size and retrospective nature. For example, there is selection bias inherent to which patients received concurrent chemotherapy versus those who did not. Additionally, the decision to treat comprehensively versus using limited fields was confounded by the overall disease status of the patient. The length of time required to treat a patient with PRDR radiation therapy (up to 1 hour for 3field comprehensive treatment) will also limit its feasibility in some contexts, especially those with very busy linear accelerators. The small sample size limits the ability to identify variables associated with recurrence, which may be important to determining those who would most benefit from reirradiation. Larger sample sizes and prospective studies will be necessary to evaluate the efficacy of concurrent chemotherapy going forward.
Conclusions This study highlights the feasibility of treating with PRDR radiation therapy and concurrent capecitabine. One advantage of this approach is the very high complete response rate observed. This compares favorably to prior studies and requires further investigation. Unique to this methodology is the ability to reirradiate both large volumes and deep tissues rather than the limited volumes commonly used with other reirradiation techniques. This approach also offers the flexibility to be performed on any linear accelerator without any additional equipment, thus expanding its availability over hyperthermia or surface brachytherapy. It also allows treatment of deep tissues, in contrast to superficial hyperthermia and brachytherapy. The use of capecitabine as an adjunct to PRDR was well tolerated and convenient. Taken collectively, our results demonstrate that PRDR with concurrent chemotherapy is a safe and effective technique that can be used for chest wall reirradiation. Radiobiologic principles suggest that a
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reduced dose rate should limit late toxicity. We speculate that late toxicity was similar to that observed in prior studies due to our larger treatment volumes. Further delineation of the safety and efficacy of PRDR therapy will require prospective controlled clinical trials.
12.
13.
References 14. 1. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), McGale P, Taylor C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: Meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383:21272135. 2. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet. 2005;366:2087-2106. 3. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002;347:1233-1241. 4. Beck TM, Hart NE, Woodard DA, Smith CE. Local or regionally recurrent carcinoma of the breast: results of therapy in 121 patients. J Clin Oncol. 1983;1:400-405. 5. Dahlstrom KK, Andersson AP, Andersen M, Krag C. Wide local excision of recurrent breast cancer in the thoracic wall. Cancer. 1993;72:774-777. 6. Auoragh A, Strnad V, Ott OJ, Beckmann MW, Fietkau R. Reirradiation of the chest wall for local breast cancer recurrence: Results of salvage brachytherapy with hyperthermia. Strahlenther Onkol. 2016;192:617-623. 7. Harms W, Krempien R, Hensley FW, Berns C, Wannenmacher M, Fritz P. Results of chest wall reirradiation using pulsed-dose-rate (PDR) brachytherapy molds for breast cancer local recurrences. Int J Radiat Oncol Biol Phys. 2001;49:205-210. 8. Linthorst M, Baaijens M, Wiggenraad R, et al. Local control rate after the combination of re-irradiation and hyperthermia for irresectable recurrent breast cancer: Results in 248 patients. Radiother Oncol. 2015;117:217-222. 9. Linthorst M, van Geel AN, Baaijens M, et al. Re-irradiation and hyperthermia after surgery for recurrent breast cancer. Radiother Oncol. 2013;109:188-193. 10. Muller AC, Eckert F, Heinrich V, Bamberg M, Brucker S, Hehr T. Re-surgery and chest wall re-irradiation for recurrent breast cancer: A second curative approach. BMC Cancer. 2011;11:197. 11. Oldenborg S, Griesdoorn V, van Os R, et al. Reirradiation and hyperthermia for irresectable locoregional recurrent breast cancer in
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previously irradiated area: Size matters. Radiother Oncol. 2015;117: 223-228. Vernon CC, Hand JW, Field SB, et al. Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: Results from five randomized controlled trials. International Collaborative Hyperthermia Group. Int J Radiat Oncol Biol Phys. 1996;35:731-744. Wahl AO, Rademaker A, Kiel KD, et al. Multi-institutional review of repeat irradiation of chest wall and breast for recurrent breast cancer. Int J Radiat Oncol Biol Phys. 2008;70:477-484. Marples B, Collis SJ. Low-dose hyper-radiosensitivity: Past, present, and future. Int J Radiat Oncol Biol Phys. 2008;70:13101318. Meyer JE, Finnberg NK, Chen L, et al. Tissue TGF-beta expression following conventional radiotherapy and pulsed low-dose-rate radiation. Cell Cycle. 2017;16:1171-1174. Short SC, Kelly J, Mayes CR, Woodcock M, Joiner MC. Low-dose hypersensitivity after fractionated low-dose irradiation in vitro. Int J Radiat Biol. 2001;77:655-664. Joiner MC, Marples B, Lambin P, Short SC, Turesson I. Low-dose hypersensitivity: Current status and possible mechanisms. Int J Radiat Oncol Biol Phys. 2001;49:379-389. Tome WA, Howard SP. On the possible increase in local tumour control probability for gliomas exhibiting low dose hyperradiosensitivity using a pulsed schedule. Br J Radiol. 2007;80:32-37. Marin LA, Smith CE, Langston MY, Quashie D, Dillehay LE. Response of glioblastoma cell lines to low dose rate irradiation. Int J Radiat Oncol Biol Phys. 1991;21:397-402. Adkison JB, Tome W, Seo S, et al. Reirradiation of large-volume recurrent glioma with pulsed reduced-dose-rate radiotherapy. Int J Radiat Oncol Biol Phys. 2011;79:835-841. Richards GM, Tome WA, Robins HI, et al. Pulsed reduced dose-rate radiotherapy: A novel locoregional retreatment strategy for breast cancer recurrence in the previously irradiated chest wall, axilla, or supraclavicular region. Breast Cancer Res Treat. 2009;114:307-313. Witt JS, Musunuru HB, Bayliss RA, Howard SP. Large volume reirradiation for recurrent meningioma with pulsed reduced dose rate radiotherapy. J Neurooncol. 2019;141:103-109. Ma CM, Lin MH, Dai XF, et al. Investigation of pulsed low dose rate radiotherapy using dynamic arc delivery techniques. Phys Med Biol. 2012;57:4613-4626. Wapnir IL, Price KN, Anderson SJ, et al. Efficacy of chemotherapy for er-negative and er-positive isolated locoregional recurrence of breast cancer: Final analysis of the CALOR trial. J Clin Oncol. 2018;36:1073-1079. Halverson KJ, Perez CA, Kuske RR, Garcia DM, Simpson JR, Fineberg B. Isolated local-regional recurrence of breast cancer following mastectomy: Radiotherapeutic management. Int J Radiat Oncol Biol Phys. 1990;19:851-858. Merino T, Tran WT, Czarnota GJ. Re-irradiation for locally recurrent refractory breast cancer. Oncotarget. 2015;6:35051-35062.
www.practicalradonc.org
Basic Original Report
Pulsed Reduced Dose Rate for Reirradiation of Recurrent Breast Cancer Adam R. Burr, MD, PhD H. Ian Robins, MD, PhD R. Adam Bayliss, PhD and Steven P. Howard, MD, PhD* Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Carbone Cancer Center, Madison, Wisconsin Received 6 March 2019; revised 15 August 2019; accepted 6 September 2019
Abstract Purpose: Locoregionally recurrent breast cancer within a previously irradiated field requires weighing the benefits of reirradiation against the increased rates of toxicity. Here we evaluate the outcomes of patients treated with pulsed reduced dose rate (PRDR) radiation therapy with concurrent low-dose capecitabine as a method to increase the therapeutic ratio of re-treatment. Methods and Materials: Patients treated from November 2000 to June 1, 2018 with PRDR radiation therapy at University of Wisconsin were identified. Patients were re-treated to a median dose of 54 Gy (range, 37.5-66 Gy) using PRDR radiation therapy, delivering radiation at an apparent dose rate of 6.67 cGy/min to allow for increased sublethal damage repair of normal tissues. The median cumulative dose was 109.8 Gy. Twenty-two patients were treated with concurrent capecitabine, most frequently at 500 mg twice per day. The KaplaneMeier method was used for survival analysis, and Cox regression analysis was used for univariate and multivariate analysis. Results: Forty-three patients were identified who underwent reirradiation for locoregionally recurrent invasive breast cancer, with a median follow-up of 20.5 months. Twenty-four patients had gross disease. Nineteen patients had simultaneous metastatic disease. The complete response rate was 83.3% in treated patients with gross disease. Locoregional recurrenceefree survival was 81.3% and 73.8% for all patients at 1 and 2 years, respectively. Overall survival for patients with localized disease was 95.7% at 1 year and 91.1% at 2 years. The rate of acute grade 3 radiation dermatitis was 25.6% with no other acute grade 3 toxicities. Grade 3 late toxicity occurred in 18.6% of patients. Conclusions: PRDR radiation therapy with capecitabine was a well-tolerated and effective method for treating patients with recurrent breast cancer. Prospective studies are necessary to compare side effects and efficacy with conventional dose rate reirradiation and to evaluate the potential role for capecitabine in the recurrent setting. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.
Sources of support: This work had no specific funding. Disclosures: none. * Corresponding author: Steven P. Howard, MD, PhD; E-mail: [email protected] https://doi.org/10.1016/j.prro.2019.09.004 1879-8500/Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.
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Introduction
Methods and Materials
Locoregional recurrence of breast cancer within a prior radiation therapy treatment field occurs at a rate of 5% to 15%.1-3 Given the prevalence of breast cancer, this is a challenging situation that will be encountered by the majority of practitioners. In the case of recurrence within the intact breast, this can often be managed with mastectomy alone without the need for reirradiation. However, a subset of cases will have unresectable recurrences, inflammatory recurrences, multiple positive nodes, or positive margins where radiation may be beneficial. Previous studies have shown that in the absence of radiation, recurrence risk after resection of a chest wall recurrence approaches 50% to 70%.4,5 However, given the increased risks of chest wall reirradiation and fibrosis associated with reirradiation, the use of radiation in this context remains controversial. Prior studies evaluating the use of reirradiation after chest wall recurrences have often focused on hyperthermia or superficial brachytherapy as potential treatments to limit the long-term side effects of radiation while maintaining efficacy.6-13 However, hyperthermia is a specialized technique that is difficult to standardize and not universally available. Superficial brachytherapy is similarly specialized and is generally not appropriate for axillary or supraclavicular recurrences. The feasibility of pulsed reduced dose rate (PRDR) radiation therapy as a technique for radiation therapy has been previously demonstrated in several systems.14-19 This technique is believed to limit normal tissue toxicity through improved sublethal damage repair at low dose rates and decreased TGF-b release compared with conventional dose rate radiation therapy.14,15 PRDR radiation therapy may also have therapeutic advantages in terms of tumor control owing to the phenomenon of low-dose hypersensitivity, which has been demonstrated in several model systems.16-19 Another potential advantage of this method is that it can be delivered at any radiation therapy center without the need for specialized techniques such as hyperthermia or brachytherapy. An additional advantage over superficial hyperthermia and brachytherapy techniques is the ability to treat deep-seated recurrences. In brief, we deliver 0.2 Gy pulses every 3 minutes to achieve an effective dose rate of 0.067 Gy/min, using a simple timer to control the delivery of the dose. We have frequently combined this with low-dose capecitabine, a convenient oral radiosensitizing chemotherapy, in an attempt to improve the efficacy of reirradiation. Here, we present our experience with PRDR radiation therapy with concurrent capecitabine as a method for the treatment of recurrent breast cancer.
Patient selection and characteristics All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study did not involve animals. Informed consent was obtained from all individual participants included in the study. A total of 43 patients were included in this study and received reirradiation to an area of locoregional recurrence of breast cancer. Forty-two patients had primary breast histology, and 1 was treated for chest wall angiosarcoma. Seventeen patients were identified from a previously published manuscript,20 and their clinical data were updated here. An additional 24 patients who had been treated at the University of Wisconsin between July 30, 2008, and June 1, 2018, were identified through billing codes and the Aria software package (Varian, Palo Alto, CA). Two additional patients were seen in consultation and follow-up at the University of Wisconsin but were treated at the Beloit Cancer Center which was formerly a satellite facility of University of Wisconsin. Patients who were candidates for reirradiation had completed their prior course of radiation at least 6 months before reirradiation. Patients with localized disease were treated for the following indications: uresectable gross disease, microscopic positive margins, lymph node involvement, or inflammatory recurrence. Patients with metastatic disease were treated to the areas of locoregional recurrence if systemic disease burden was well controlled at the time and the disease was found to be progressing locoregionally. In these cases, the prevention of locoregional progression and associated morbidity was thought to outweigh the risks. Patient characterization at the time of initial diagnosis is included in Table 1. Nineteen patients underwent mastectomy at the time of initial diagnosis. Of the 24 patients who underwent breast-conserving surgery at the time of diagnosis, none underwent reirradiation to the intact breast. All underwent either subsequent mastectomy or radiation to the supraclavicular and axillary region alone. Thirty-four patients underwent initial axillary dissection, with 31 having initial nodal involvement. Breast tangents alone were delivered to 24 patients, and 15 underwent comprehensive irradiation at the time of initial diagnosis. Four patients subsequently received nodal irradiation after breast tangents owing to axillary or supraclavicular recurrence before PRDR therapy. One patient received mantle irradiation as treatment for Hodgkin lymphoma. The median total initial radiation dose was 59.4 Gy.
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Summary of patient characteristics
Patient characteristics, initial surgery, and initial radiation
Nodal status Yes No Axillary dissection At time of breast surgery Delayed dissection No Mastectomy At time of diagnosis Delayed mastectomy No Initial radiation Median dose (range), Gy Breast tangents alone Comprehensive nodal irradiation Metachronous nodal irradiation Mantle
All Patients
No concurrent chemotherapy
Concurrent chemotherapy
31 12
14 6
17 6
29 1 13
13 1 6
16 0 7
19 13 11
5 8 7
14 5 4
P value 1
.55
.06
59.4 (48.6-181.8) 15 21 6 1
Characterization of disease status at the time of recurrence is included in Table 2. Positron emission tomography/computed tomography (CT) restaging was performed for 72% of patients before reirradiation, with CT of the chest, abdomen, and pelvis performed for the remainder. Fourteen patients were re-treated for isolated chest wall recurrences, 14 patients were re-treated for isolated nodal recurrences, and 15 patients were re-treated for multisubsite recurrences. A total of 24 patients were treated for gross disease, 14 patients were treated for microscopically positive margins, and 5 patients were treated with adjuvant therapy. Indications for adjuvant treatment included inflammatory recurrence (2 patients) and extensive nodal involvement (3 patients). Ten patients had additional locoregional recurrences before PRDR radiation. After completion of therapy, the complete response rate was defined by clinical examination in all cases, with the addition of imaging in 70% of cases. Local recurrence was defined as recurrence within the treatment field. Locoregional recurrence was defined as recurrence on the chest wall, axilla, supraclavicular, or internal mammary region. Progression occurred in 3 patients adjacent to the field overlying the humerus, overlying the scapula, and on the anterior abdominal wall. This was considered a distant progression because it was outside of a reasonable radiation field. Progression-free survival was defined, consistent with previous consensus, as freedom from distant progression or death. Assessment of overall survival was augmented using Social Security death searches for patients who were lost to follow-up. Toxicity was scored by Common Terminology Criteria for Adverse Events version 5 for both early and late effects of radiation therapy, except for rib fracture, which was scored in a
59.4 (50-107.8) 7 9 4 0
59.4 (45-181.8) 8 12 2 1
.58
binary manner. Toxicities were only scored if they were new or worsened after radiation therapy. Acute toxicity was specified as toxicity that occurred within 90 days after radiation therapy; chronic toxicity occurred thereafter. Median follow-up was calculated from the initial day of PRDR until the date of last follow-up (Table 2). The median follow-up for all patients was 20.5 months (range, 0.5-147.0 months).
Radiation therapy Field and dose Twenty-two patients were treated with reirradiation with curative intent. Nineteen patients were treated with palliative intent because of metastatic disease at the time of treatment of local disease. Two additional patients were treated with palliative intent, which was indicated at the time of consultation, because of gross disease involvement of brachial plexus. The reirradiation field was confined to a single site in 28 cases, and comprehensive 3- or 4-field radiation was delivered in 15 cases (Table 2). Comprehensive irradiation was defined as irradiation of the chest wall, the axillary nodal region, and the supraclavicular region. The entire region (ie, chest wall, axillary, and supraclavicular) was included in the planning target volume (PTV), with the regions defined similarly to the Radiation Therapy Oncology Group contouring atlas. If gross disease was present, a generous expansion of 1 to 1.5 cm was included, and the PTV was expanded accordingly. Only fields that were previously irradiated were treated with PRDR radiation. Thus, if a woman had received whole-breast radiation with tangents previously and had a chest wall recurrence, only the chest wall would be treated
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A.R. Burr et al Summary of recurrence at re-treatment characteristics
Patient no. Median age (range), y Median follow-up from PRDR, mo Median time to reirradiation, mo Site of recurrence Isolated chest wall Isolated axillary Isolated SCV Isolated IM Multisite Disease burden Gross Microscopic Adjuvant >1 local relapse Yes No Metastases at time of recurrence Yes No Median reirradiation dose (range), Gy Median cumulative dose (range), Gy Median tumor volume (range), cm3 Median volume V95% (range), cm3 Reirradiation site Chest wall only Axillary only SCV only IM only Axillary and SCV Chest wall and axilla Comprehensive
All patients
No concurrent chemotherapy
Concurrent chemotherapy
43 56 (34-80) 20.5 (0.5-147.0) 36.7 (7.9-269.0)
20 63 (45-77) 29.4 (0.5-147.0) 45.2 (14.0-265.0)
23 49 (34-80) 18.2 (1.3-50.4) 29.3 (7.7-269.0)
P value
.37 .43 .43
14 6 6 2 15
5 5 3 0 7
9 1 3 2 8
.22
24 14 5
10 5 5
14 9 0
.04
10 33
7 17
3 16
.29
19 24 54 (30-70) 110 (75-235.8) 42.2 (1-497) 1137 (51-3098)
7 13 54 (30-66) 112 (75-157.8) 21 (4.8-295) 1207.5 (126-3082)
12 11 54 (37.5-70) 110.5 (75-235.8) 46.1 (1-497) 1137 (51-3098)
.27
9 6 3 1 6 2 16
3 3 0 0 5 1 8
.52 .55 .46 .42 .28
6 3 3 1 1 1 8
Abbreviations: IM Z internal mammary; PRDR Z pulsed reduced-dose rate; SCV Z supraclavicular.
with PRDR. The axillary or supraclavicular fields would then be treated with a standard dose rate. The median volume receiving 50% of the radiation dose was 2053 cm3, whereas 1099 cm3 received 95% of the prescription dose. The median point maximum was 115% of prescription due in part to planning constraints of PRDR and to the use of electrons in 7 cases. The prescription re-treatment dose varied from 30 to 70 Gy with a median dose of 54 Gy. The median cumulative dose delivered was 109.6 Gy. Four patients were treated with electrons (9-15 MeV), 35 with photons, 4 with mixed electrons and photons. Two patients were treated with a standard dose rate. PRDR technique As technology has evolved, PRDR delivery has also changed, though the dose rate has remained 0.067 Gy/ min.20-22 All patients underwent CT simulation in a wing board. A standard 3- or 4-field postmastectomy, monoisocentric, 3-dimensional (3D) conformal radiation
therapy technique was used for the majority of patients in this study. The targets were contoured as noted earlier, and the fields were designed to encompass the entire PTV target with a 7-to-10-mm margin to block edge. Five millimeters of bolus was used when treating the chest wall. Four patients were treated with electrons only, 35 patients underwent 3D conformal techniques, and 4 patients were treated with static intensity modulated radiation therapy (IMRT; Varian, True Beam, Palo Alto, CA). The specifics of these techniques are discussed in the following. The simplest cases included in this study were those treated with electrons only to chest wall recurrences, for which the total number of calculated monitor units was divided into segments of 20 cGy and the corresponding segment was delivered every 3 minutes. The 20 cGy “pulse” was delivered at a dose rate of 100 MU/min, which was the lowest dose rate available on Varian EX and Trilogy accelerators. For all cases, regardless of technique,
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a digital timer was started at the beginning of each segment, with the following segment started when the timer read 3 minutes. Patients were treated with 0.5 cm of bolus or wet gauze. The 3D conformal technique was used for the vast majority of cases on this study. The advantage of 3D conformal radiation therapy was that in a 3- or 4-field plan, treatment could alternate between the chest wall and axillary/ supraclavicular fields, treating each every 3 minutes and dramatically decreasing treatment times. Generally, field-in-field radiation therapy was not used, so the total number of monitor units per field could be divided by 10 and delivered in 20-cGy segments every 3 minutes, as noted. Physical wedges were used for the majority of patients treated with 3D conformal radiation therapy. Continuous dose rate with volumetric modulated arc therapy was attempted for low-dose-rate treatments at our institution using the advanced treatment modes on the Varian TrueBeam, which allowed continuous delivery of as low as 5 MU/min. Ultimately, it was found that an excess number of faults was occurring, which lengthened treatment time. As a result, static IMRT has since been adopted for all future PRDR plans that use photons. The general method is described in detail by Witt et al.22 Briefly, the challenge with IMRT delivery of PRDR is the variation in dose rate inherent to target and at-risk structures. We have chosen to use the method of Ma et al to limit the average target dose rate to 0.067 Gy/min with a maximum of 0.133 Gy/min.23 Using this technique, we calculate a meter rate and compare the maximum meter rates to choose the lowest meter rate per field. Typically, 7 beams are used per field, with a minimum of 6 MU per segment and a minimum segment size of 6 cm2. We have not routinely used dose constraints, but since implementing IMRT, we have constrained the brachial plexus to less than 105% of the prescription dose.
Chemotherapy Concurrent chemotherapy was administered to 23 patients, and 20 patients received no concurrent chemotherapy. The group that received chemotherapy was more likely to have had a mastectomy at the time of initial diagnosis (P Z .02). Twenty-two patients were treated with concurrent daily capecitabine. Initially, this was dosed at 500 mg in the morning and 1000 mg in the evening (5 patients). We currently treat with 500 mg twice daily to limit short-term toxicity (13 patients). Two patients had unknown capecitabine dosing, and 2 received 650 mg twice daily. One patient was treated with liposomal doxorubicin 40 mg/m2 administered every 2 weeks.
Statistics Statistical analysis was performed using SPSS (IBM, Armonk, NY). The KaplaneMeier method was used to
Summary of patient characteristics
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evaluate local recurrence, locoregional recurrence, progression-free survival, and overall survival. Fisher’s exact test and Pearson’s c2 test were used to compare patients who received concurrent chemotherapy with those who did not.
Results Disease control Among patients with gross disease, the in-field complete response rate was 83.3%. The overall local control rate for all patients in this study was 88.7%, 73.8%, and 71.4% at 1, 2, and 5 years, respectively, after completion of therapy (Fig 1). The locoregional control rate was 81.3%, 73.8%, 60.4% at 1, 2, and 5 years, respectively (Fig 1). Among patients with gross disease, the rate of local control was 78.1%, 57.0%, and 57.0% and locoregional control was 64.8%, 55.5%, and 44.4% at 1, 2, and 5 years, respectively (Fig 1). In patients with microscopic disease, 2 of 12 patients had a locoregional failure with a 1-year locoregional control of 90.9%. Patients with localized disease at the time of reirradiation had overall survival rates of 95.7% and 91.1% at 1 and 2 years, respectively (Fig 1). For patients with localized disease, progression-free survival rates were 82.5% at 1 year and 73.1% at 2 years (Fig 1). Patients with metastatic disease had overall survival rates of 47.4% at 1 year and 17.8% at 2 years (Fig 1). Patients with metastatic disease had progression-free survival rates of 22.2% at 1 year and 16.7% at 2 years (Fig 1). As expected, the progressionfree survival difference was statistically significant between patients with local and metastatic disease.
Univariate and multivariate analysis In an attempt to determine variables associated with treatment outcomes, Cox regression analysis was performed (Table 3). On univariate analysis, a disease-free interval of less than 30 months (median) and the presence of metastatic disease were associated with increased locoregional recurrence and worse overall survival. A Karnofsky performance status score of 80 or less, a reirradiation dose <50 Gy, capecitabine use, and presence of gross disease were correlated with decreased overall survival but not locoregional recurrence. Interestingly, estrogen receptor status, isolated chest wall recurrence, multisite recurrence, and multiple prior recurrences were not correlated with outcome in this study. On multivariable analysis, disease-free interval and metastatic disease were correlated with decreased locoregional control. Disease-free interval, metastatic disease, and a Karnofsky Performance Status score of 80 were correlated with decreased overall survival.
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0.6 0.4 All patients
0.2 0
Proportion free of recurrence
B
12
24 36 48 months Locoregional recurrence free survival
0
C
24
36 months
48
60
0 12
24 months
36
48
60
Locoregional recurrence free survival 0.8 0.6 0.4
Adjuvant Microscopic Gross
0.2 0 0
12
24 36 months
48
60
Overall survival 1
Localized Metastatic
0.8
0.2
F
Locoregional recurrence free survival 1
Adjuvant Microscopic Gross
0.4
1
All patients
12
0.6
E
0.6
0
0.8
0
0.8
0.2
1
60
1
0.4
Local recurrence free survival
Proportion free of recurrence
0.8
0
Proportion free of recurrence
D
Local Recurrence Free Survival 1
Proportion free of recurrence
Proportion free of recurrence
A
Proportion surviving
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0.6 0.4 0.2
0.8 0.6 0.4
Localized Metastatic
0.2 0
0 0
12
24
36
48
60
0
months
12
24 months
36
48
60
Figure 1 Local control for (A) all patients and (D) treated patients with gross, microscopic, or adjuvant disease. Locoregional control for (B) all patients and (E) treated patients with gross, microscopic, and adjuvant disease. (C) Locoregional control and (F) overall survival for treated patients with localized and metastatic disease.
Toxicity Overall, reirradiation with PRDR radiation therapy was well tolerated, with no grade 4 or 5 toxicities. Acute and Table 3
chronic toxicities are summariezed in Table 4. Acute grade 2 dermatitis occurred in 20 patients (46.5%), whereas grade 3 dermatitis occurred in 11 patients (25.6%). This was equal between patients who received
Univariate and multivariate analysis of variables associated with locoregional recurrence and overall survival
Univariate analysis Disease free interval >30 mo Metastatic disease Local vs comprehensive XRT Reirradiation dose <50 Gy Complete response KPS 80 Capecitabine Gross vs microscopic or adjuvant ER-negative Isolated CW Multiple subsite recurrence Multiple prior recurrences Multivariate Disease-free interval Metastatic disease KPS 80 Reirradiation dose <50
LRR HR
P value
95% CI
OS HR
P value
95% CI
7.14 6.59 0.71 1.82 0.35 1.98 1.72 3.54 2.29 1.08 0.70 0.69
.01 .003 .59 .58 .08 .32 .39 .06 .20 .91 .60 .58
(1.52-33.44) (1.86-23.36) (0.21-2.46) (3.66-31.21) (0.11-1.15) (0.52-7.54) (0.50-5.89) (0.97-12.98) (0.60-8.78) (0.28-4.17) (0.19-2.64) (0.19-2.57)
3.67 4.49 0.73 10.69 1.76 2.83 2.47 3.22 1.67 1.12 1.85 0.93
.003 .00006 .45 .00002 .121 .02 .03 .005 .22 .78 .14 .87
(1.56-8.64) (2.18-10.57) (0.32-1.66) (3.66-31.21) (0.86-3.62) (1.21-6.61) (1.10-5.55) (1.43-7.22) (0.73-3.80) (0.51-2.46) (0.82-4.14) (0.41-2.13)
12.01 12.17 -
.004 .002 -
2.22-65.0 2.60-57.0 -
4.90 7.42 4.01 7.48
.001 .0003 .01 .002
(1.85-12.98) (2.51-21.87) (1.35-12.98) (2.51-21.87)
Abbreviations: CI Z confidence interval; CW Z chest wall; ER Z estrogen receptor; HR Z hazard ratio; KPS Z Karnofsky performance status; LRR Z locoregional recurrence; OS Z overall survival; XRT Z radiation therapy.
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concurrent chemotherapy and those who did not. Among patients treated to the supraclavicular region, 6 of 12 (50%) receiving capecitabine developed grade 1 esophagitis, although no esophagitis was noted among the 13 patients who did not receive capecitabine. Chronic toxicity did not appear to be increased by concurrent chemotherapy. Five patients (12.8%) required hyperbaric oxygen or wound vac placement to heal. Grade 3 lymphedema occurred in 1 patient, with a total of 6 patients developing new grade 1 or 2 lymphedema after treatment. Chronic fibrosis was the most common side effect, occurring in 8 patients (20.5%). Three rib fractures occurred among 38 patients receiving over 100 Gy in cumulative dose to the ribs. Grade 3 fibrosis occurred in 2 patients, grade 2 fibrosis occurred in 3 patients, and grade 1 fibrosis occurred in 3 patients. The total rate of chronic grade 3 toxicity was 16.3%. There was no difference in frequency of grade 3 side effects between patients treated with capecitabine and those who were not. There was a single case of brachial plexopathy in a patient who received axillary and supraclavicular reirradiation for a gross recurrence 12 years before the complication. Her main symptom is mild weakness; she does not have pain or sensory changes. Magnetic resonance imaging of the brachial plexus showed matting and enhancing of the nerves with loss of fat planes. The cumulative radiation dose was 50.4 Gy initially followed 4 years later by 54 Gy without concurrent capcitabine. A total of 33 patients with a median follow-up of 18.6 months received reirradiation to the brachial plexus with a median dose of 110.8 Gy with no additional cases of brachial plexopathy.
Discussion The current study demonstrates the safety and efficacy of PRDR radiation therapy in combination with capecitabine as a method for re-treatment of locoregional breast cancer. The local and locoregional control rates from this study are comparable to those in prior studies. Interestingly, locoregional control was decreased in patients with metastatic disease at the time of diagnosis. Even if 2 patients treated to doses <50 Gy are excluded, the decreased locoregional control remains significant in these patients. There was an increased rate of patients with gross disease in the group treated for metastatic disease (P Z .01). Additionally, when present, the median amount of gross disease was greater at 46 mL versus 21 mL, though this did not reach statistical significance (P Z .47). Neither comprehensive radiation fields nor concurrent chemotherapy was used more frequently in localized versus metastatic disease. Thus, although the difference in control may be due in part to differences in disease burden, caution should be exercised when treating
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Summary of patient characteristics Table 4
Summary of acute and chronic toxicity
Acute toxicity
Acute dermatitis Grade 1 Grade 2 Grade 3 Acute esophagitis Grade 1 Chronic toxicity Chronic lymphedema Grade 1 Grade 2 Grade 3 Chronic fibrosis Grade 1 Grade 2 Grade 3 Necrosis Grade 1 Grade 2 Grade 3 Brachial plexopathy Grade 1
Concurrent P All No chemotherapy value patients concurrent chemotherapy .96 11 20 11
5 10 5
6 10 6
6
0
6 .5
5 1 1
3 0 1
2 1 0 .34
5 3 2
2 3 1
3 0 1
0 0 5
0 0 4
0 0 1
.19
.36 1
1
0
patients without significant symptoms because metastatic patients appear to have less durable locoregional control. In this study, the complete response rate of 83.3% was higher than that observed in the majority of prior studies (Table 5). This rate of complete response with the moderate, median dose of 54 Gy supports the concept of low-dose hypersensitivity. Despite the improvement in complete response rates, 5-year local control and locoregional control were comparable to those in prior studies. Thus, it appears that in several patients, microscopic disease persisted through chemoradiation therapy and regrew at a later date. Several possibilities exist to combat this problem, including increasing radiation dose, potentially through a concomitant boost to gross disease or increasing capecitabine dose. Additional adjuvant systemic therapy strategies could also potentially improve long-term rates of disease control. It remains an open question whether concurrent chemotherapy with capecitabine significantly improves outcomes within this population. There did not appear to be an adverse quantitative feature that was substantially worse in the capecitabine group to explain the worse outcomes. Importantly, although there was an increase in esophagitis rates with concurrent capecitabine, no increase was observed in long-term toxicity. Ultimately,
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Table 5
Review of reirradiation literature Patient no.
Treatment modality and median dose
Range of years
Local recurrence free survival, % (y)
Locoregional recurrenceefree survival, y
Complete response rate, %
Wahl, 200813
81
1993-2005
53 (1) with gross disease, 100 without
NR
57 (67 with hyperthermia and 35 without)
Linthorst, 20158
1996-2011
53 40 39 8 78
Oldenborg, 201511
248 with gross disease 198 patients with microscopic disease or adjuvant 414
External beam radiation with chemotherapy (54%) and hyperthermia (54%), 48 Gy 32 Gy in biweekly 4-Gy fractions with weekly hyperthermia 32 Gy in biweekly 4-Gy fractions with weekly hyperthermia
Auoragh, 20166
18
Muller, 201110
42
Vernon, 199612
306
Harms, 20007
58
Merino, 201524
47
Linthorst, 20139
4.9
1
N/A
11.9
1982-2005
25 (3)
58
24
2004-2011
56 (5)
75
17
1993-2003
62 (5)
NR
19
1988-1991
25 (3) with RT alone versus 45 with RT and hyperthermia* 89 (1) gross 81 (2) gross 75 (3) gross 67 (1) 50 (2)
59 combined (41 with RT alone)
NR
93.3
60.3 (majority g3 telangiectasias)
1993-1999
2008-2013
Abbreviations: CW Z chest wall; NR Z not reported; PDR Z pulsed dose rate; RT Z radiation therapy. * From graph.
14.9
Practical Radiation Oncology: --- 2019
32 Gy in biweekly 4 Gy fractions with weekly hyperthermia 56 Gy with superficial brachytherapy, 5/23 treatments with concurrent chemotherapy 60 Gy external beam with hyperthermia in 29 Results of 5 randomized trials comparing to RT alone versus RT and hyperthermia Two fractions of 20 Gy using PDR brachytherapy EBRT to mean of cumulative dose of 99.8 Gy to breast and CW
1993-2010
(1) (3) (5) (3) (5)
Late grade 3 toxicity, %
A.R. Burr et al
Study
Practical Radiation Oncology: --- 2019
randomized data are needed to support the use of concurrent chemotherapy; however, until that time, these data provide an estimation of the risk of the addition of capecitabine to chest wall irradiation. At our institution, our practice has evolved to currently offer concurrent chemotherapy to the vast majority of patients with microscopic or gross disease and good performance status. An even more central question is the patients for whom reirradiation is indicated. Certainly, in patients with localized, gross residual disease, radiation appears to allow a chance at cure. Thirty-four percent of patients in this study remained disease free at 5 years after radiation for localized, gross disease. This likely underestimates the true rate of disease control, considering many patients treated in the past several years remain disease free with limited followup. Additionally, we treated 15 metastatic patients with gross, locoregional disease with palliative intent to prevent the significant morbidity and pain associated with locoregional progression. A more challenging clinical judgment must be made in terms of treating patients with microscopic disease or treating in an adjuvant fashion after negative margin resection. Prior studies showed local recurrence rates of 50% to 70% in patients after the excision of chest wall recurrences.4,5 Linthorst et al demonstrated 78% locoregional control at 5 years in patients treated with reirradiation and hyperthermia after complete resection or resection with positive margins, suggesting some benefit to radiation after resection. One would expect this benefit to be greatest in patients with positive margins, for whom the 50% to 70% recurrence rates may be accurate. Indeed, the recently completed Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer trial mandated radiation for patients with positive margin status.25 Local or locoregional failure occurred first in 16 of 158 patients on this trial. Thus, in patients with negative margins, a 50% to 70% recurrence rate likely overestimates the true rate of recurrence in a modern setting. We suggest treating these patients only for high-risk features such as inflammatory recurrence, supraclavicular recurrence, extensive extracapsular extension, or >4 lymph nodes involved. Further work will be especially valuable in assessing subgroups without gross residual disease, for whom radiation can be omitted. After the decision is made to treat with radiation therapy, the radiation field must be defined. Although not associated with increased risk of locoregional recurrence on univariate or multivariate analysis, 3 of 28 patients treated with radiation to a subsite had their first site of locoregional recurrence occur within a standard comprehensive 3-field radiation plan. Thus, comprehensive radiation would have had benefit for a subset of patients and should be considered for those treated curatively. We did not have any instances of failure in internal mammary lymph nodes after reirradiation, and we standardly omit treatment of these lymph nodes unless they are clinically involved.
Summary of patient characteristics
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The potential benefit of reirradiation must be weighed against the risk. The rate of acute grade 3 toxicity in this study was 25.6%. In the palliative context, this rate of toxicity, which incurs significant pain, must be weighed against potential palliative benefit. The grade 3 late toxicity rate was 20.3%, which is similar to 4 prior studies6,10,11,26 but substantially greater than several other studies.8,9,13,26 Interestingly, the rate of late grade 3 toxicity varied from 1% to 24% across 3 studies treating with 32 Gy in 4 Gy biweekly fractions with hyperthermia, demonstrating a challenge in reporting retrospective toxicity data. Smoking and diabetes were not statistically associated with increased rates of toxicity in our study, though we do counsel patients with these comorbidities that they are theoretically at increased risk of complication. No variables were associated with increased rates of toxicity in this study, and larger studies will likely be needed to better identify variables associated with substantial risk of toxicity. The weaknesses of this study include its relatively small sample size and retrospective nature. For example, there is selection bias inherent to which patients received concurrent chemotherapy versus those who did not. Additionally, the decision to treat comprehensively versus using limited fields was confounded by the overall disease status of the patient. The length of time required to treat a patient with PRDR radiation therapy (up to 1 hour for 3field comprehensive treatment) will also limit its feasibility in some contexts, especially those with very busy linear accelerators. The small sample size limits the ability to identify variables associated with recurrence, which may be important to determining those who would most benefit from reirradiation. Larger sample sizes and prospective studies will be necessary to evaluate the efficacy of concurrent chemotherapy going forward.
Conclusions This study highlights the feasibility of treating with PRDR radiation therapy and concurrent capecitabine. One advantage of this approach is the very high complete response rate observed. This compares favorably to prior studies and requires further investigation. Unique to this methodology is the ability to reirradiate both large volumes and deep tissues rather than the limited volumes commonly used with other reirradiation techniques. This approach also offers the flexibility to be performed on any linear accelerator without any additional equipment, thus expanding its availability over hyperthermia or surface brachytherapy. It also allows treatment of deep tissues, in contrast to superficial hyperthermia and brachytherapy. The use of capecitabine as an adjunct to PRDR was well tolerated and convenient. Taken collectively, our results demonstrate that PRDR with concurrent chemotherapy is a safe and effective technique that can be used for chest wall reirradiation. Radiobiologic principles suggest that a
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Practical Radiation Oncology: --- 2019
A.R. Burr et al
reduced dose rate should limit late toxicity. We speculate that late toxicity was similar to that observed in prior studies due to our larger treatment volumes. Further delineation of the safety and efficacy of PRDR therapy will require prospective controlled clinical trials.
12.
13.
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