- Email: [email protected]
Efficacy of Concurrent Chemoradiotherapy for Patients With Locally Recurrent or Advanced Inoperable Breast Cancer
Original Study
Efficacy of Concurrent Chemoradiotherapy for Patients With Locally Recurrent or Advanced Inoperable Breast Cancer Joseph N. Shaughnessy,1 Richard A. Meena,1 Neal E. Dunlap,1 Dharamvir Jain,2 Elizabeth C. Riley,2 Amy R. Quillo,3 Anthony E. Dragun1 Abstract Patients with locally advanced, neglected, recurrent, or metastatic inoperable breast cancer, or a combination of these conditions, may live for an extended period as a result of effective systemic therapy. Durable local control is needed to control symptomatic tumors. Twenty patients received concurrent chemoradiotherapy (CRT), with an overall response rate of 100%, 2-year local relapse-free survival of 73%, and acceptable toxicity. Background: This study aimed to assess the efficacy and safety of chemoradiotherapy (CRT) for locally recurrent or advanced inoperable breast cancer. Patients and Methods: Twenty patients treated between 2009 and 2013 were reviewed from a prospectively collected database. All patients had symptomatic recurrent or advanced breast cancer and had been deemed not to be ideal operative candidates. Treatment consisted of external beam radiotherapy to the primary tumor in the breast or regional lymph nodes, or both, concurrent with either capecitabine, paclitaxel, or cisplatin/etoposide chemotherapy. The grade of acute and late toxicity was evaluated, as was response to treatment, overall survival (OS), and local relapse-free survival (LRFS). Results: Of the 20 patients, 9 (45%) presented with primary disease and 11 (55%) had recurrent disease. A total of 11 (55%) patients had evidence of metastatic disease. The overall clinical response rate was 100%, with a clinical complete response (CR) observed in 65% of patients and a clinical partial response (PR) observed in 35% of patients. At a median follow up of 25.3 months, 2-year LRFS was 73% and 2-year OS was 80%. Local control was significantly better in patients with an initial diagnosis (hazard ratio [HR], 0.139; 95% confidence interval [CI], 0.014-0.935) and in those who had not had previous in-field radiation (HR, 0.011; 95% CI, 0.005-0.512). The only grade 3 toxicity was acute dermatologic events (30%) and late dermatologic (15%) events. Conclusion: Concurrent CRT with capecitabine, paclitaxel, or cisplatin/etoposide for recurrent or advanced inoperable breast cancer is well tolerated with impressive clinical response rates and durable local control. Clinical Breast Cancer, Vol. 15, No. 2, 135-42 ª 2015 Elsevier Inc. All rights reserved. Keywords: Chemotherapy, CRT, Local disease, Radiotherapy, Unresectable
Introduction Breast cancer is the most commonly diagnosed malignancy in women, with a lifetime risk of approximately 12%.1 Most patients present with early-stage disease and are candidates for surgical 1
Department Department Department University of 2 3
of Radiation Oncology of Medical Oncology of Surgical Oncology Louisville James Graham Brown Cancer Center, Louisville, KY
Submitted: Apr 30, 2014; Revised: Oct 14, 2014; Accepted: Oct 16, 2014; Epub: Oct 22, 2014 Address for correspondence: Joseph N. Shaughnessy, MD, Department of Radiation Oncology, James Graham Brown Cancer Center, 529 S Jackson St, Louisville, KY 40202 E-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2014.10.007
resection, with consideration for the addition of radiotherapy or chemotherapy, or both. However, a smaller percentage of individuals present with more advanced disease and are less likely to be treated surgically because of a variety of factors, including disseminated metastases or very locally advanced disease. In the past, these patients could be managed effectively with primary radiotherapy, with distant disease progression soon becoming their primary source of morbidity and mortality.2 Currently armed with everimproving systemic therapies—including optimization of chemotherapeutic regimens and hormonal manipulations, as well as novel targeted agents—these patients are seeing continued gains in survival.3 In this setting, the management of local disease becomes increasingly important because patients are living for extended periods with the potential sequelae of locally advanced disease such as
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Concurrent CRT for Inoperable Breast Cancer Table 1 Patient, Tumor, and Treatment Characteristics No. of Patients
Table 3 Recurrent Disease Characteristics
20
Age, years (median, range)
57 (39-85)
Primary Disease (no. patients)
45% (9)
Recurrent Disease
55% (11)
Nonmetastatic (no. patients)
45% (9)
Metastatic (no. patients)
55% (11)
Type of Recurrence No chest wall recurrence Chest wall recurrence Inflammatory recurrence
No Nodal Involvement
Nodal Involvement
e 2 (2) 1
5 (1) 2 1
Values in parentheses represent subset with M1 disease.
Receptor Status Estrogen receptor positive (no. patients)
60% (12)
Progesterone receptor positive (no. patients)
30% (6)
Her2/neu amplified (no. patients)
20% (4)
Radiation Dose
4500 cGy (2000-6600)
Fraction size
300 cGy (120-300)
In-field repeated irradiation (no. patients)
15% (3)
Chemotherapy Delivered Capecitabine (no. patients)
60% (12)
Paclitaxel (no. patients)
30% (6)
Cisplatin/etoposide (no. patients)
10% (2)
chest wall pain or ulcerated lesions. External beam radiotherapy has proved effective in these situations,4-9 but a standard course of treatment may not be able to provide the extended periods of local control necessary to coincide with the duration of survival in these patients. Furthermore, it may necessitate the temporary cessation of systemic chemotherapy to deliver treatment in a manner deemed safe. Certain chemotherapeutic agents have been used concurrently as radiosensitizers in multiple disease sites, yielding improvements in local control and survival over radiation alone.10,11 Concurrent chemoradiotherapy (CRT) has been examined in breast cancer in the neoadjuvant,12 definitive,13,14 and adjuvant15-17 settings and has generally been found to be both safe and effective. In this study, we report on our experience delivering concurrent chemoradiotherapy as primary treatment in a cohort of patients with very locally advanced, neglected, or recurrent breast cancer, comparing our results with others who have used similar treatment regimens.
Figure 1 Overall Survival (OS) for the Entire Cohort
Patients and Methods Twenty consecutive patients were evaluated from a prospectively collected database of individuals treated at the University of Louisville James Graham Brown Cancer Center between 2009 and 2013 after approval by the University of Louisville Institutional Review Board. Inclusion criteria were a diagnosis of biopsy-proven locally advanced primary (stage IIIA) or recurrent breast cancer
Table 2 Primary Tumor Staging Stage
N0
N1
N2
N3
T3 T4b T4c
e e 1 (1)
1 e
e e 1 (1)
e 1 (1) 5 (5)
Values in parentheses represent subset with M1 disease.
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involving the primary site or regional lymph nodes. The patients all had symptomatic disease and were deemed not to be ideal surgical candidates because of unresectable local infiltration, metastatic disease, or poor performance status. All patients were treated with concurrent chemotherapy. Chemotherapeutic agents included capecitabine, paclitaxel, or cisplatin/etoposide. Selection of chemotherapy was at the discretion of the treating medical oncologist and was dependent on the overall clinical situation, because patients had previously been treated with various other lines of therapy. The most common agent used was single-agent capecitabine, most commonly dosed at 500 mg/m2 twice daily or 1000 mg twice daily. The second most commonly used agent was single-agent paclitaxel, typically dosed at 80 mg/m2 weekly. Chemotherapy doses were titrated as necessary depending on the clinical picture. Radiotherapy was directed to the entire breast and regional lymph nodes when possible, most commonly with tangential fields, with consideration for a supraclavicular/axillary field. An involved field was considered only in cases of repeated irradiation. Inverse planned intensity-modulated radiotherapy was considered in selected cases if the gross disease was complex and not easily encompassed by more traditional fields. Fractionation was chosen on an individual basis, with twice daily hyperfractionation being standard in the retreatment setting and conventional or hypofractionation used in previously nonirradiated patients. End points evaluated included response to treatment, local relapse-free survival (LRFS), overall survival (OS), and grade of
Joseph N. Shaughnessy et al Figure 2 Local Recurrence-Free Survival (LRFS) for the Entire Cohort
acute and late toxicity. Response was given a grade of complete response (CR), partial response (PR), stable disease, or progressive disease. Evaluation was performed using clinical examination and available imaging scans. A CR was complete resolution of treated disease; a PR was a reduction in disease of 30% or more; progressive disease was an increase in disease of 20% or more; and stable disease was any response not meeting other criteria. Pathologic response was assessed when available, with a CR defined as no residual viable disease and a PR defined as < 10 microscopic foci of disease. LRFS and OS were assessed using the Kaplan-Meier method, and univariate analyses were performed on both outcomes using the Cox proportional hazards model. A local relapse was defined as clinically or radiographically observed disease progression in the treated radiation field. All patients were seen on a weekly basis during CRT, were assessed 1 month after treatment completion, and then seen on an individualized follow-up schedule thereafter. Acute and late toxicity was scored using the Common Terminology Criteria for Adverse Events, version 3.0, with late toxicity being defined as occurring 3 months or more after treatment.
Figure 3 Local Recurrence-Free Survival (LRFS) in Patients With Primary Versus Recurrent Disease (P [ .050)
Results A total of 20 patients were included for analysis; patient, tumor, and treatment characteristics can be found in Table 1. The median duration of patient follow-up was 25.3 months (range, 1.6-42 months), and the median patient age was 57 years (range, 39-85 years). Nine (45%) patients presented with a first diagnosis of breast cancer, and 11 patients (55%) were treated in the setting of recurrent disease. Tables 2 and 3 depict the initial staging of primary tumors and description of recurrences, respectively. Eleven (55%) patients had evidence of metastatic disease, whereas disease was classified as M0 in 9 (45%) patients. All tumors were classified as invasive ductal carcinomas. Estrogen receptor, progesterone receptor, and Her2/neu positivity was 60%, 30%, and 20%, respectively.
Figure 4 Local Recurrence-Free Survival (LRFS) in Patients With or Without Previous In-Field Radiotherapy (P [ .011)
Table 4 Predictive Factors for Local Recurrence 95% CI for HR Variable Age, years Primary Metastasis ER/PR status HER2 status Radiation dose Response No previous radiotherapy
P Value
HR
Lower
Upper
.682 .050 .251 .620 .669 .989 .531 .011
0.981 0.139 2.864 1.593 1.614 0.999 0.494 0.052
0.894 0.014 0.475 0.253 0.180 1.001 0.054 0.005
1.076 0.935 17.254 10.025 14.490 1.005 4.492 0.512
Abbreviations: CI ¼ confidence interval; ER ¼ estrogen receptor; HR ¼ hazard ratio; PR ¼ progesterone receptor.
Abbreviations: ReRT ¼ repeated radiotherapy; RT ¼ radiotherapy.
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Concurrent CRT for Inoperable Breast Cancer Table 5 Predictive Factors for Overall Survival
Table 6 Toxicity
95% CI for HR Variable Age, years Primary Metastasis ER/PR status HER2 status Radiation dose Response No previous radiotherapy
P Value
HR
Lower
Upper
.195 .664 .402 .272 .593 .890 .867 .574
1.056 0.587 0.018 3.853 0.519 1.000 1.231 29.715
0.973 0.053 0.000 0.347 0.047 0.999 0.108 0.000
1.146 6.506 214.039 42.744 5.767 1.001 14.010 4,030,289.93
Abbreviations: CI ¼ confidence interval; ER ¼ estrogen receptor; HR ¼ hazard ratio; PR ¼ progesterone receptor.
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Patients received a median dose of 4500 cGy (range, 2000-6600 cGy) at a median of 300 cGy (range, 120-400 cGy) per fraction, with concurrent capecitabine, paclitaxel, or cisplatin/etoposide in 60%, 30%, and 10% of patients, respectively. A total of 3 patients (15%) were treated with repeated irradiation and received a median dose of 5040 cGy (range, 4560-5520cGy) at 120 cGy delivered in a twice-daily fashion. All patients were determined to have had at least a PR to therapy, with 13 (65%) judged to have had a CR, and 7 (35%) having had a PR. We had surgical data from 4 patients, with 1 pathologic complete response (pCR) (25%), 1 pathologic PR (25%), and 2 cases of treatment effect (50%). There were 5 local failures after a median duration of 11.2 months (range, 827.1 months), and all 3 patients treated with in-field repeated irradiation experienced local progression. At the point of last analysis, there were 3 total deaths in the patient cohort. Median OS and LRFS were not reached. Kaplan-Meier curves for both OS and LRFS can be found in Figures 1 and 2, respectively. At 2 years, there was an LRFS of 73% and an OS of 80%. Univariate analysis (Table 4) identified primary disease (hazard ratio [HR], 0.139; 95% confidence interval [CI], 0.14-0.935) (Figure 3) and no previous in-field radiotherapy (HR, 0.052; 95% CI, 0.0050.512) (Figure 4) as predictors of decreased local failure. The univariate analysis did not identify any factors that significantly influenced OS (Table 5). Table 6 presents the type and grade of each toxicity of grade 2. The most commonly experienced site of toxicity was the skin, with 80% experiencing grade 2 acute radiation dermatitis. Most of these were self-limited processes that resolved with symptomatic management. However, there were 3 late grade 4 toxicities involving 3 patients with stage T4b or T4c disease who had persistent ulceration longer than 3 months after completion of treatment. Two of these patients presented with ulceration before the initiation of treatment and account for both of the acute grade 4 skin toxicities. All 3 of these patients went on to undergo palliative mastectomies and did not experience any significant wound healing issues postoperatively. All 3 patients recovered fully from their operations and were without evidence of local disease recurrence at the time of last follow-up. Other acute toxicities experienced included grade 2 pain, fatigue, and esophagitis in 6 (30%) patients, 2 (10%) patients, and
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Event
Grade 2 (%)
Skin (acute) Skin (late) Pain (acute) Fatigue (acute) Esophagitis (acute)
10 7 6 2 3
(50) (35) (30) (10) (15)
Grade 3 (%)
Grade 4 (%)
4 (20) e e e e
2 (10) 3 (15) e e e
3 (15%) patients, respectively. All patients with esophagitis received radiation doses to portions of their esophagus as part of nodal treatment volumes. There were no observed cases of radiation pneumonitis in the patient group. Table 7 shows the incidence of grade 3 toxicity corresponding to the chemotherapeutic agent delivered concurrently with radiotherapy. Grade 3 toxicity was limited to dermatologic reactions.
Discussion Primary radiotherapy has been used for local control of breast tumors in a variety of situations2,4-9 (a summary of selected studies can be found in Table 8). Excellent local control was obtained by Chargari et al with radiation alone in early-stage tumors, with locoregional control at 7 years of 95.8%.7 Not surprisingly, however, local control dramatically diminishes with increasing tumor size and nodal burden, as demonstrated in the combined GustaveRoussy Institute and Princess Margaret Hospital experience.5 Certain chemotherapeutic agents are known radiosensitizers, allowing for an enhanced therapeutic ratio and improved tumor control when given concurrently with radiotherapy. Concurrent CRT has been used at multiple disease sites, with gains in local control, disease-free survival, and OS over radiation alone. To date, this strategy is not routinely used in the treatment of breast cancer. However, it has been investigated in a variety of situations, with promising results. The 3 chemotherapy regimens used in our population have all been used concurrently with radiotherapy in a range of other disease sites, as well as in breast cancer (Table 9). CRT has been used to treat intact breast tumors and recurrences by several institutions in both the neoadjuvant and definitive settings.12-14,18-27 Table 9 contains a breakdown of several selected studies using this approach. In those studies with surgical data, pCR rates vary from 16% to 88%. Because of different patient populations, radiotherapy doses, and chemotherapy given, it is difficult to directly compare these results. For frame of reference, a recently published meta-analysis of 12 international trials comprising 11,955
Table 7 Chemotherapy and Corresponding Grade 3/4 Toxicity Chemotherapeutic Agent
Grade 3 Acute Skin (%)
Grade 4 Acute Skin (%)
Grade 4 Late Skin (%)
Capecitabine Paclitaxel Cisplatin/etoposide
2 (17) 2 (33) 0
1 (8) 1 (17) 0
1 (8) 2 (33) 0
Table 8 Selected Studies Using Radiotherapy on Intact Breast Tumors Concurrent Chemotherapy
Response
First Author
Patients
Population
Sequencing
Radiation Dose
Pathologic
Clinical
Toxicity
Local Control
Arriagada4,5
463
Unresectable or high surgical risk/43%/T4
Radiation alone
40-45 Gy þ 0-35 Gy boost (2.5 Gy/fraction)
None
NA
60% CR 27% PR
60% LRC at 2 years
Chargari7
29
T1/T2/70þ years/refused surgery or high risk
Radiation alone
32.5 Gy þ 16 Gy boost (6.5 Gy/fraction)
None
NA
NR
Halverson8
224
Locoregional recurrence/M0
41% Resection > Radiation (41%)
45-50 Gy boost to 70 Gyb
None
NA
NR
Huang9
38
Inoperable after chemotherapy/M0/68%/T4
Radiation > surgery (84%)
Median 50 Gy (range 30-65 Gy)b þ 4-15 Gy boost in 21%
13% received concurrent 5-fluorouracil
5% CR
13% CR 13% PR
Zucali2
454
T3-T4NxM0
Radiation > surgery (29%)
40-45 Gy (kV) or 60-70 Gy (cobalt-60)b
None
10% CR
50% CR
Latea: 9% grade 2þ shoulder 4% grade 2þ skin 1% grade 2 pneumonitis 3% grade 2 edema Acute: 0% grade 3þ skin Late: 11% lymphedema 75.9% good cosmesis Latea: 4% grade 2þ edema 2% grade 2þ skin, pneumonitis, rib fracture 53% “significant postoperative morbidity” at 5 years NR
57% LRC at 5 years
64% LRC at 5 years
24% first site of local recurrence
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Abbreviations: CR ¼ complete response; LRC ¼ locoregional control; NA ¼ not applicable; NR ¼ not reported; PR ¼ partial response. a 0-3 toxicity scale used. b 1.8-2 Gy/fraction.
95.8% LRC at 7 years
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140
First Author
Population
Sequencing
Radiation Dose
105
IIB-IIIC
112
IIB-IIIB
Bollet19,20
59
IIA-IIIA
Neoadjuvant CRT > surgery Neoadjuvant CRT > surgery Neoadjuvant CRT > surgery
45 Gy þ 14 Gy boost 50 Gy þ 10 Gy boost 50 Gy
MMC/5-FU or Gem/CDDP 5-FU/vinorelbine
Chakravarthy21
38
IIA-IIIB
Neoadjuvant CRT > surgery
46.8 Gy
Feyerabend22
25
Formenti24
44
Inoperable recurrence/M0-1 IIB-IIIB
Formenti23
35
T3/T4/unresectable
Genet25
66
Inflammatory (M0)
Kao26
16
IIIB-IIIC
Definitive CRT þ hyperthermia Neoadjuvant CRT > surgery Neoadjuvant CRT > surgery Neoadjuvant CRT > surgery CRT surgery (81%)
Karasawa13
35
IIIB-IV/recurrent
Definitive CRT
Karasawa14
39
T4/M0-1
Definitive CRT
IIB-IIIB
Neoadjuvant CRT > surgery
Adams
18
Alvarado-Miranda12
Shanta27
Patients
Concurrent Chemotherapy
1117
a
Paclitaxel
Response Pathologic
Clinical
Toxicity
Local Control
23% CR, 11% PR 30% CR
NR
NR
NR
NR
Acute: 22.4% grade 3 skin Acute: 14% grade 3 skin Late: 8% grade 3 skin Acute: 3.3% grade 3, 3.3% grade 4 skin 2 flap revisions Acute: 16% grade 3 skin Acute: 7% grade 3 skin 14% postoperative complication Acute: 25.7% grade 2þ skin 1 late skin toxicity 6 rib fractures Acute: 43% grade 3, 6% grade 4 Late: 13% grade 3 skin, 6% grade 3 lymphedema, 6% grade 3 joint Acute: 3% grade 3/4 skin, 3% grade 3 pneumonitis Acute: 23% grade 3 skin, 3% grade 3 pneumonitis NR
1 local recurrence 97% LC 90% LRC at 5 years NR
27% CR
20% CR 34% PR
Paclitaxel
34% CR
18% CR
Mean 49.4 Gy (36-70 Gy)b 45 Gy
Epirubicin/ifosfamide
NA
50 Gy
5-FU
45 Gyc þ 24-26 Gy boost Median 60 Gy (54-69 Gy)
5-FU/CDDP
Median 60 Gy (54-69 Gy) Median 60 Gy (59-66 Gy) 40 Gy
Paclitaxel
44% CR 36% PR 16% CR 18% 80% CR 11% PR PR 20% CR 14% 11% CR 60% PR PR 88% CR 88% CR
Paclitaxel vinorelbine
56% CR
NR
Docetaxel
NA
Docetaxel or paclitaxel CMF or CAF
NA
68% CR 28% PR 41% CR 53% PR NR
45% CR
5 mo median LC NR NR NR 83% LRC
NR 74% LC at 2 years 7% local failure (crude)
Abbreviations: CAF ¼ cyclophosphamide, doxorubicin, 5-fluorouracil; CDDP ¼ cisplatin; CMF ¼ cyclophosphamide, methotrexate, 5-fluorouracil; CR ¼ complete response; CRT ¼ chemoradiotherapy; 5-FU ¼ 5-fluorouracil; Gem ¼ gemcitabine; LC ¼ local control; LRC ¼ locoregional control; MMC ¼ mitomycin; NA ¼ not applicable; NR ¼ not reported; PR ¼ partial response. a All radiation delivered at 1.8-2 Gy/fraction unless indicated. b 32% treated at 1.2 Gy twice daily. c 1.5 Gy twice daily for 5 d every 4 wk.
Concurrent CRT for Inoperable Breast Cancer
Clinical Breast Cancer April 2015
Table 9 Selected Studies Using Concurrent Chemoradiotherapy on Intact Breast Tumors
Joseph N. Shaughnessy et al patients demonstrated an overall pCR rate with neoadjuvant chemotherapy of 13% to 22%, depending on how pCR was defined.28 Although a good surrogate marker for efficacy of treatment and a known positive prognosticator in those receiving neoadjuvant treatment, pCR rates can be influenced by factors including stage27 and tumor receptor status,29 again impairing direct comparison. Pathologic partial response has also been shown to be a positive prognostic factor.18,23 When reported, it varied between 11% and 18% in the CRT studies examined and was typically defined as a significant reduction in tumor with < 10 microscopic foci of residual disease. In the 2 studies with available pathologic data on patients receiving radiation alone for intact breast tumors, pCR rates were only 5% to 10%.2,9 These results, when taken together, show a higher rate of pathologic sterilization when using CRT compared with radiation alone. These results are not particularly surprising and would presumably translate into more sustained local tumor control, although no head-to-head comparisons exist. Because our series was mainly nonsurgical, response was judged clinically, with a clinical CR rate of 65% and a clinical PR rate of 35%. This was on the higher end of the range seen in other radiotherapy and CRT trials that reported clinical response data (Tables 8 and 9). Although this rate of clinical response was encouraging, especially given the advanced disease in our patient population, one can see from the aforementioned tables that clinical and pathologic response do not always go hand in hand. There can be significant discordance of up to 64% (clinical CR 80% vs. pathologic CR 16%), as seen in the study of Formenti et al.24 Additionally, the concept of clinical response is dependent on the assessor, with some degree of subjectivity at play. What was more encouraging was our 2-year LRFS of 73%. This was nearly identical to the 74% local control at 2 years found in a study by Karasawa et al, which used CRT as definitive therapy in a very similar patient population.14 Of the 5 local failures noted during our follow-up period, 3 were patients with recurrent disease treated with hyperfractionated repeated irradiation, which has been shown by others to be a risk factor for decreased tumor control.22 The 2-year OS of 80% in this high-risk population, with 55% of patients having metastatic disease at the time of treatment, is a testament to both the nature of breast cancer and the ever-improving systemic therapies, making long-lasting local therapy an essential component of care. A unique aspect of our study was the common use of hypofractionated radiotherapy. Although several of the radiation-alone studies used hypofractionation with success, with Arriagada et al4,5 using 2.5 Gy per fraction and Chargari et al treating with doses of 6.5 Gy per fraction, the CRT experiences were primarily with standard fractionation.7 The median total dose and dose per fraction in our study were 4500 cGy and 300 cGy, respectively. A total of 9 (45%) patients received this exact fractionation schedule as part of their treatment. There has been a recent trend toward hypofractionation in the adjuvant setting, with studies using dosing regimens similar to ours demonstrating equivalence to conventional fractionation in both recurrence rate and overall toxicity.30-32 A very similar fractionation schedule was used in the START A (UK Standardisation of Breast Radiotherapy Trial), in which a dose of 41.6 Gy was used at 3.2 Gy per fraction, with no increase in acute
or late toxicity at a median follow-up of 5 years.30 Just as in the START A and B trials, we were also comfortable using hypofractionation to treat nodal volumes when appropriate. Our treatment approach has evolved to prefer a hypofractionated approach because it allows for increased patient convenience with no observed detrimental effect on outcomes. Treatment was well tolerated in our patient population, with the majority of toxicity resolving with symptomatic treatment. Acute skin toxicity was the most common toxicity, which was consistent with other studies. Our rates may have been affected by the high number of patients with skin involvement at presentation, clouding proper assessment of treatment effect versus tumor involvement. Three patients with stage T4b or T4c disease did undergo eventual mastectomy for persistent ulceration > 3 months after treatment and were scored as having grade 4 toxicities. All 3 patients had uneventful postoperative courses and remained locoregionally disease free at last follow-up. Other larger neoadjuvant studies have reported higher rates of postoperative complications of up to 14%.24 If it is determined that a patient would benefit from surgery after treatment, we believe that the downstaging and long-term tumor control afforded by CRT outweigh the relatively low risk of postoperative complications. Pneumonitis, rib fracture, and lymphedema have been observed at acceptable rates in other larger studies but were not noted in our series. As more patients are treated with this approach and longer term follow-up accrues, additional toxicity may occur. Although cosmesis is not typically of primary concern in this specific population, the phase III ARCOSEIN trial looked at sequential versus concurrent chemotherapy and radiotherapy in the adjuvant setting after breast-conserving surgery and found no different in patient overall satisfaction with cosmetic outcome.16
Conclusion Patients treated with concurrent CRT in our series experienced marked tumor regression, with durable local disease control and acceptable treatment-related toxicity. Treatment did not preclude surgical resection if deemed necessary or potentially advantageous. Hypofractionated regimens were also used in our series safely and effectively. CRT is a viable treatment approach in patients with metastatic or unresectable disease in whom long-term local control is desired.
Clinical Practice Points Most patients with breast cancer are diagnosed with early-stage
disease and are eligible for surgical resection. A minority of patients will present with locally advanced or
metastatic disease, or both, and may be poor operative candidates for a variety of reasons. These may include poor performance status, extensive local infiltration, or patient preference. These patients are seeing continued gains in survival through the advancement of systemic therapies, including both chemotherapy regimens and novel targeted agents. Radiotherapy can be used to palliate the symptoms of locoregional tumor burden in these patients with modest success. Certain chemotherapeutic agents have been used as radiosensitizers at a multitude of disease sites, with gains in local control.
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Concurrent CRT for Inoperable Breast Cancer CRT has been used in breast cancer in several settings, including
neoadjuvant, definitive, and adjuvant approaches. This study details our institutional experience using concurrent
CRT for definitive local control in inoperable breast cancer. We saw impressive results in local control, with a favorable toxicity profile. Furthermore, we demonstrated that using a hypofractionated approach in this setting is safe and effective.
Disclosure The authors have stated that they have no conflicts of interest.
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14. Karasawa K, Saito M, Hirowatari H, et al. The role of chemoradiotherapy in patients with unresectable T4 breast tumors. Breast Cancer 2013; 20:254-61. 15. Haffty BG, Kim JH, Yang Q, Higgins SA. Concurrent chemo-radiation in the conservative management of breast cancer. Int J Radiat Oncol Biol Phys 2006; 66: 1306-12. 16. Toledano AH, Bollet MA, Fourquet A, et al. Does concurrent radiochemotherapy affect cosmetic results in the adjuvant setting after breast-conserving surgery? Results of the ARCOSEIN multicenter, phase III study: patients’ and doctors’ views. Int J Radiat Oncol Biol Phys 2007; 68:66-72. 17. Toledano A, Azria D, Garaud P, et al. Phase III trial of concurrent or sequential adjuvant chemoradiotherapy after conservative surgery for early-stage breast cancer: final results of the ARCOSEIN trial. J Clin Oncol 2007; 25:405-10. 18. Adams S, Chakravarthy AB, Donach M, et al. Preoperative concurrent paclitaxelradiation in locally advanced breast cancer: pathologic response correlates with fiveyear overall survival. Breast Cancer Res Treat 2010; 124:723-32. 19. Bollet MA, Belin L, Reyal F, et al. Preoperative radio-chemotherapy in early breast cancer patients: long-term results of a phase II trial. Radiother Oncol 2012; 102:82-8. 20. Bollet MA, Sigal-Zafrani B, Gambotti L, et al. Pathological response to preoperative concurrent chemo-radiotherapy for breast cancer: results of a phase II study. Eur J Cancer 2006; 42:2286-95. 21. Chakravarthy AB, Kelley MC, McLaren B, et al. Neoadjuvant concurrent paclitaxel and radiation in stage II/III breast cancer. Clin Cancer Res 2006; 12: 1570-6. 22. Feyerabend T, Wiedemann GJ, Jager B, Vesely H, Mahlmann B, Richter E. Local hyperthermia, radiation, and chemotherapy in recurrent breast cancer is feasible and effective except for inflammatory disease. Int J Radiat Oncol Biol Phys 2001; 49:1317-25. 23. Formenti SC, Dunnington G, Uzieli B, et al. Original p53 status predicts for pathological response in locally advanced breast cancer patients treated preoperatively with continuous infusion 5-fluorouracil and radiation therapy. Int J Radiat Oncol Biol Phys 1997; 39:1059-68. 24. Formenti SC, Volm M, Skinner KA, et al. Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin-based chemotherapy in locally advanced breast cancer: a phase I/II trial. J Clin Oncol 2003; 21:864-70. 25. Genet D, Lejeune C, Bonnier P, et al. Concomitant intensive chemoradiotherapy induction in non-metastatic inflammatory breast cancer: long-term follow-up. Br J Cancer 2007; 97:883-7. 26. Kao J, Conzen SD, Jaskowiak NT, et al. Concomitant radiation therapy and paclitaxel for unresectable locally advanced breast cancer: results from two consecutive phase I/II trials. Int J Radiat Oncol Biol Phys 2005; 61:1045-53. 27. Shanta V, Swaminathan R, Rama R, Radhika R. Retrospective analysis of locally advanced noninflammatory breast cancer from Chennai, South India, 1990-1999. Int J Radiat Oncol Biol Phys 2008; 70:51-8. 28. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and longterm clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; 384:164-72. 29. Lee HC, Ko H, Seol H, et al. Expression of immunohistochemical markers before and after neoadjuvant chemotherapy in breast carcinoma, and their use as predictors of response. J Breast Cancer 2013; 16:395-403. 30. Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol 2008; 9:331-41. 31. Bentzen SM, Agrawal RK, Aird EG, et al. The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet 2008; 371:1098-107. 32. Whelan TJ, Pignol JP, Levine MN, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 2010; 362:513-20.
Efficacy of Concurrent Chemoradiotherapy for Patients With Locally Recurrent or Advanced Inoperable Breast Cancer Joseph N. Shaughnessy,1 Richard A. Meena,1 Neal E. Dunlap,1 Dharamvir Jain,2 Elizabeth C. Riley,2 Amy R. Quillo,3 Anthony E. Dragun1 Abstract Patients with locally advanced, neglected, recurrent, or metastatic inoperable breast cancer, or a combination of these conditions, may live for an extended period as a result of effective systemic therapy. Durable local control is needed to control symptomatic tumors. Twenty patients received concurrent chemoradiotherapy (CRT), with an overall response rate of 100%, 2-year local relapse-free survival of 73%, and acceptable toxicity. Background: This study aimed to assess the efficacy and safety of chemoradiotherapy (CRT) for locally recurrent or advanced inoperable breast cancer. Patients and Methods: Twenty patients treated between 2009 and 2013 were reviewed from a prospectively collected database. All patients had symptomatic recurrent or advanced breast cancer and had been deemed not to be ideal operative candidates. Treatment consisted of external beam radiotherapy to the primary tumor in the breast or regional lymph nodes, or both, concurrent with either capecitabine, paclitaxel, or cisplatin/etoposide chemotherapy. The grade of acute and late toxicity was evaluated, as was response to treatment, overall survival (OS), and local relapse-free survival (LRFS). Results: Of the 20 patients, 9 (45%) presented with primary disease and 11 (55%) had recurrent disease. A total of 11 (55%) patients had evidence of metastatic disease. The overall clinical response rate was 100%, with a clinical complete response (CR) observed in 65% of patients and a clinical partial response (PR) observed in 35% of patients. At a median follow up of 25.3 months, 2-year LRFS was 73% and 2-year OS was 80%. Local control was significantly better in patients with an initial diagnosis (hazard ratio [HR], 0.139; 95% confidence interval [CI], 0.014-0.935) and in those who had not had previous in-field radiation (HR, 0.011; 95% CI, 0.005-0.512). The only grade 3 toxicity was acute dermatologic events (30%) and late dermatologic (15%) events. Conclusion: Concurrent CRT with capecitabine, paclitaxel, or cisplatin/etoposide for recurrent or advanced inoperable breast cancer is well tolerated with impressive clinical response rates and durable local control. Clinical Breast Cancer, Vol. 15, No. 2, 135-42 ª 2015 Elsevier Inc. All rights reserved. Keywords: Chemotherapy, CRT, Local disease, Radiotherapy, Unresectable
Introduction Breast cancer is the most commonly diagnosed malignancy in women, with a lifetime risk of approximately 12%.1 Most patients present with early-stage disease and are candidates for surgical 1
Department Department Department University of 2 3
of Radiation Oncology of Medical Oncology of Surgical Oncology Louisville James Graham Brown Cancer Center, Louisville, KY
Submitted: Apr 30, 2014; Revised: Oct 14, 2014; Accepted: Oct 16, 2014; Epub: Oct 22, 2014 Address for correspondence: Joseph N. Shaughnessy, MD, Department of Radiation Oncology, James Graham Brown Cancer Center, 529 S Jackson St, Louisville, KY 40202 E-mail contact: [email protected]
1526-8209/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clbc.2014.10.007
resection, with consideration for the addition of radiotherapy or chemotherapy, or both. However, a smaller percentage of individuals present with more advanced disease and are less likely to be treated surgically because of a variety of factors, including disseminated metastases or very locally advanced disease. In the past, these patients could be managed effectively with primary radiotherapy, with distant disease progression soon becoming their primary source of morbidity and mortality.2 Currently armed with everimproving systemic therapies—including optimization of chemotherapeutic regimens and hormonal manipulations, as well as novel targeted agents—these patients are seeing continued gains in survival.3 In this setting, the management of local disease becomes increasingly important because patients are living for extended periods with the potential sequelae of locally advanced disease such as
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Concurrent CRT for Inoperable Breast Cancer Table 1 Patient, Tumor, and Treatment Characteristics No. of Patients
Table 3 Recurrent Disease Characteristics
20
Age, years (median, range)
57 (39-85)
Primary Disease (no. patients)
45% (9)
Recurrent Disease
55% (11)
Nonmetastatic (no. patients)
45% (9)
Metastatic (no. patients)
55% (11)
Type of Recurrence No chest wall recurrence Chest wall recurrence Inflammatory recurrence
No Nodal Involvement
Nodal Involvement
e 2 (2) 1
5 (1) 2 1
Values in parentheses represent subset with M1 disease.
Receptor Status Estrogen receptor positive (no. patients)
60% (12)
Progesterone receptor positive (no. patients)
30% (6)
Her2/neu amplified (no. patients)
20% (4)
Radiation Dose
4500 cGy (2000-6600)
Fraction size
300 cGy (120-300)
In-field repeated irradiation (no. patients)
15% (3)
Chemotherapy Delivered Capecitabine (no. patients)
60% (12)
Paclitaxel (no. patients)
30% (6)
Cisplatin/etoposide (no. patients)
10% (2)
chest wall pain or ulcerated lesions. External beam radiotherapy has proved effective in these situations,4-9 but a standard course of treatment may not be able to provide the extended periods of local control necessary to coincide with the duration of survival in these patients. Furthermore, it may necessitate the temporary cessation of systemic chemotherapy to deliver treatment in a manner deemed safe. Certain chemotherapeutic agents have been used concurrently as radiosensitizers in multiple disease sites, yielding improvements in local control and survival over radiation alone.10,11 Concurrent chemoradiotherapy (CRT) has been examined in breast cancer in the neoadjuvant,12 definitive,13,14 and adjuvant15-17 settings and has generally been found to be both safe and effective. In this study, we report on our experience delivering concurrent chemoradiotherapy as primary treatment in a cohort of patients with very locally advanced, neglected, or recurrent breast cancer, comparing our results with others who have used similar treatment regimens.
Figure 1 Overall Survival (OS) for the Entire Cohort
Patients and Methods Twenty consecutive patients were evaluated from a prospectively collected database of individuals treated at the University of Louisville James Graham Brown Cancer Center between 2009 and 2013 after approval by the University of Louisville Institutional Review Board. Inclusion criteria were a diagnosis of biopsy-proven locally advanced primary (stage IIIA) or recurrent breast cancer
Table 2 Primary Tumor Staging Stage
N0
N1
N2
N3
T3 T4b T4c
e e 1 (1)
1 e
e e 1 (1)
e 1 (1) 5 (5)
Values in parentheses represent subset with M1 disease.
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involving the primary site or regional lymph nodes. The patients all had symptomatic disease and were deemed not to be ideal surgical candidates because of unresectable local infiltration, metastatic disease, or poor performance status. All patients were treated with concurrent chemotherapy. Chemotherapeutic agents included capecitabine, paclitaxel, or cisplatin/etoposide. Selection of chemotherapy was at the discretion of the treating medical oncologist and was dependent on the overall clinical situation, because patients had previously been treated with various other lines of therapy. The most common agent used was single-agent capecitabine, most commonly dosed at 500 mg/m2 twice daily or 1000 mg twice daily. The second most commonly used agent was single-agent paclitaxel, typically dosed at 80 mg/m2 weekly. Chemotherapy doses were titrated as necessary depending on the clinical picture. Radiotherapy was directed to the entire breast and regional lymph nodes when possible, most commonly with tangential fields, with consideration for a supraclavicular/axillary field. An involved field was considered only in cases of repeated irradiation. Inverse planned intensity-modulated radiotherapy was considered in selected cases if the gross disease was complex and not easily encompassed by more traditional fields. Fractionation was chosen on an individual basis, with twice daily hyperfractionation being standard in the retreatment setting and conventional or hypofractionation used in previously nonirradiated patients. End points evaluated included response to treatment, local relapse-free survival (LRFS), overall survival (OS), and grade of
Joseph N. Shaughnessy et al Figure 2 Local Recurrence-Free Survival (LRFS) for the Entire Cohort
acute and late toxicity. Response was given a grade of complete response (CR), partial response (PR), stable disease, or progressive disease. Evaluation was performed using clinical examination and available imaging scans. A CR was complete resolution of treated disease; a PR was a reduction in disease of 30% or more; progressive disease was an increase in disease of 20% or more; and stable disease was any response not meeting other criteria. Pathologic response was assessed when available, with a CR defined as no residual viable disease and a PR defined as < 10 microscopic foci of disease. LRFS and OS were assessed using the Kaplan-Meier method, and univariate analyses were performed on both outcomes using the Cox proportional hazards model. A local relapse was defined as clinically or radiographically observed disease progression in the treated radiation field. All patients were seen on a weekly basis during CRT, were assessed 1 month after treatment completion, and then seen on an individualized follow-up schedule thereafter. Acute and late toxicity was scored using the Common Terminology Criteria for Adverse Events, version 3.0, with late toxicity being defined as occurring 3 months or more after treatment.
Figure 3 Local Recurrence-Free Survival (LRFS) in Patients With Primary Versus Recurrent Disease (P [ .050)
Results A total of 20 patients were included for analysis; patient, tumor, and treatment characteristics can be found in Table 1. The median duration of patient follow-up was 25.3 months (range, 1.6-42 months), and the median patient age was 57 years (range, 39-85 years). Nine (45%) patients presented with a first diagnosis of breast cancer, and 11 patients (55%) were treated in the setting of recurrent disease. Tables 2 and 3 depict the initial staging of primary tumors and description of recurrences, respectively. Eleven (55%) patients had evidence of metastatic disease, whereas disease was classified as M0 in 9 (45%) patients. All tumors were classified as invasive ductal carcinomas. Estrogen receptor, progesterone receptor, and Her2/neu positivity was 60%, 30%, and 20%, respectively.
Figure 4 Local Recurrence-Free Survival (LRFS) in Patients With or Without Previous In-Field Radiotherapy (P [ .011)
Table 4 Predictive Factors for Local Recurrence 95% CI for HR Variable Age, years Primary Metastasis ER/PR status HER2 status Radiation dose Response No previous radiotherapy
P Value
HR
Lower
Upper
.682 .050 .251 .620 .669 .989 .531 .011
0.981 0.139 2.864 1.593 1.614 0.999 0.494 0.052
0.894 0.014 0.475 0.253 0.180 1.001 0.054 0.005
1.076 0.935 17.254 10.025 14.490 1.005 4.492 0.512
Abbreviations: CI ¼ confidence interval; ER ¼ estrogen receptor; HR ¼ hazard ratio; PR ¼ progesterone receptor.
Abbreviations: ReRT ¼ repeated radiotherapy; RT ¼ radiotherapy.
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Concurrent CRT for Inoperable Breast Cancer Table 5 Predictive Factors for Overall Survival
Table 6 Toxicity
95% CI for HR Variable Age, years Primary Metastasis ER/PR status HER2 status Radiation dose Response No previous radiotherapy
P Value
HR
Lower
Upper
.195 .664 .402 .272 .593 .890 .867 .574
1.056 0.587 0.018 3.853 0.519 1.000 1.231 29.715
0.973 0.053 0.000 0.347 0.047 0.999 0.108 0.000
1.146 6.506 214.039 42.744 5.767 1.001 14.010 4,030,289.93
Abbreviations: CI ¼ confidence interval; ER ¼ estrogen receptor; HR ¼ hazard ratio; PR ¼ progesterone receptor.
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Patients received a median dose of 4500 cGy (range, 2000-6600 cGy) at a median of 300 cGy (range, 120-400 cGy) per fraction, with concurrent capecitabine, paclitaxel, or cisplatin/etoposide in 60%, 30%, and 10% of patients, respectively. A total of 3 patients (15%) were treated with repeated irradiation and received a median dose of 5040 cGy (range, 4560-5520cGy) at 120 cGy delivered in a twice-daily fashion. All patients were determined to have had at least a PR to therapy, with 13 (65%) judged to have had a CR, and 7 (35%) having had a PR. We had surgical data from 4 patients, with 1 pathologic complete response (pCR) (25%), 1 pathologic PR (25%), and 2 cases of treatment effect (50%). There were 5 local failures after a median duration of 11.2 months (range, 827.1 months), and all 3 patients treated with in-field repeated irradiation experienced local progression. At the point of last analysis, there were 3 total deaths in the patient cohort. Median OS and LRFS were not reached. Kaplan-Meier curves for both OS and LRFS can be found in Figures 1 and 2, respectively. At 2 years, there was an LRFS of 73% and an OS of 80%. Univariate analysis (Table 4) identified primary disease (hazard ratio [HR], 0.139; 95% confidence interval [CI], 0.14-0.935) (Figure 3) and no previous in-field radiotherapy (HR, 0.052; 95% CI, 0.0050.512) (Figure 4) as predictors of decreased local failure. The univariate analysis did not identify any factors that significantly influenced OS (Table 5). Table 6 presents the type and grade of each toxicity of grade 2. The most commonly experienced site of toxicity was the skin, with 80% experiencing grade 2 acute radiation dermatitis. Most of these were self-limited processes that resolved with symptomatic management. However, there were 3 late grade 4 toxicities involving 3 patients with stage T4b or T4c disease who had persistent ulceration longer than 3 months after completion of treatment. Two of these patients presented with ulceration before the initiation of treatment and account for both of the acute grade 4 skin toxicities. All 3 of these patients went on to undergo palliative mastectomies and did not experience any significant wound healing issues postoperatively. All 3 patients recovered fully from their operations and were without evidence of local disease recurrence at the time of last follow-up. Other acute toxicities experienced included grade 2 pain, fatigue, and esophagitis in 6 (30%) patients, 2 (10%) patients, and
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Event
Grade 2 (%)
Skin (acute) Skin (late) Pain (acute) Fatigue (acute) Esophagitis (acute)
10 7 6 2 3
(50) (35) (30) (10) (15)
Grade 3 (%)
Grade 4 (%)
4 (20) e e e e
2 (10) 3 (15) e e e
3 (15%) patients, respectively. All patients with esophagitis received radiation doses to portions of their esophagus as part of nodal treatment volumes. There were no observed cases of radiation pneumonitis in the patient group. Table 7 shows the incidence of grade 3 toxicity corresponding to the chemotherapeutic agent delivered concurrently with radiotherapy. Grade 3 toxicity was limited to dermatologic reactions.
Discussion Primary radiotherapy has been used for local control of breast tumors in a variety of situations2,4-9 (a summary of selected studies can be found in Table 8). Excellent local control was obtained by Chargari et al with radiation alone in early-stage tumors, with locoregional control at 7 years of 95.8%.7 Not surprisingly, however, local control dramatically diminishes with increasing tumor size and nodal burden, as demonstrated in the combined GustaveRoussy Institute and Princess Margaret Hospital experience.5 Certain chemotherapeutic agents are known radiosensitizers, allowing for an enhanced therapeutic ratio and improved tumor control when given concurrently with radiotherapy. Concurrent CRT has been used at multiple disease sites, with gains in local control, disease-free survival, and OS over radiation alone. To date, this strategy is not routinely used in the treatment of breast cancer. However, it has been investigated in a variety of situations, with promising results. The 3 chemotherapy regimens used in our population have all been used concurrently with radiotherapy in a range of other disease sites, as well as in breast cancer (Table 9). CRT has been used to treat intact breast tumors and recurrences by several institutions in both the neoadjuvant and definitive settings.12-14,18-27 Table 9 contains a breakdown of several selected studies using this approach. In those studies with surgical data, pCR rates vary from 16% to 88%. Because of different patient populations, radiotherapy doses, and chemotherapy given, it is difficult to directly compare these results. For frame of reference, a recently published meta-analysis of 12 international trials comprising 11,955
Table 7 Chemotherapy and Corresponding Grade 3/4 Toxicity Chemotherapeutic Agent
Grade 3 Acute Skin (%)
Grade 4 Acute Skin (%)
Grade 4 Late Skin (%)
Capecitabine Paclitaxel Cisplatin/etoposide
2 (17) 2 (33) 0
1 (8) 1 (17) 0
1 (8) 2 (33) 0
Table 8 Selected Studies Using Radiotherapy on Intact Breast Tumors Concurrent Chemotherapy
Response
First Author
Patients
Population
Sequencing
Radiation Dose
Pathologic
Clinical
Toxicity
Local Control
Arriagada4,5
463
Unresectable or high surgical risk/43%/T4
Radiation alone
40-45 Gy þ 0-35 Gy boost (2.5 Gy/fraction)
None
NA
60% CR 27% PR
60% LRC at 2 years
Chargari7
29
T1/T2/70þ years/refused surgery or high risk
Radiation alone
32.5 Gy þ 16 Gy boost (6.5 Gy/fraction)
None
NA
NR
Halverson8
224
Locoregional recurrence/M0
41% Resection > Radiation (41%)
45-50 Gy boost to 70 Gyb
None
NA
NR
Huang9
38
Inoperable after chemotherapy/M0/68%/T4
Radiation > surgery (84%)
Median 50 Gy (range 30-65 Gy)b þ 4-15 Gy boost in 21%
13% received concurrent 5-fluorouracil
5% CR
13% CR 13% PR
Zucali2
454
T3-T4NxM0
Radiation > surgery (29%)
40-45 Gy (kV) or 60-70 Gy (cobalt-60)b
None
10% CR
50% CR
Latea: 9% grade 2þ shoulder 4% grade 2þ skin 1% grade 2 pneumonitis 3% grade 2 edema Acute: 0% grade 3þ skin Late: 11% lymphedema 75.9% good cosmesis Latea: 4% grade 2þ edema 2% grade 2þ skin, pneumonitis, rib fracture 53% “significant postoperative morbidity” at 5 years NR
57% LRC at 5 years
64% LRC at 5 years
24% first site of local recurrence
Joseph N. Shaughnessy et al
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Abbreviations: CR ¼ complete response; LRC ¼ locoregional control; NA ¼ not applicable; NR ¼ not reported; PR ¼ partial response. a 0-3 toxicity scale used. b 1.8-2 Gy/fraction.
95.8% LRC at 7 years
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140
First Author
Population
Sequencing
Radiation Dose
105
IIB-IIIC
112
IIB-IIIB
Bollet19,20
59
IIA-IIIA
Neoadjuvant CRT > surgery Neoadjuvant CRT > surgery Neoadjuvant CRT > surgery
45 Gy þ 14 Gy boost 50 Gy þ 10 Gy boost 50 Gy
MMC/5-FU or Gem/CDDP 5-FU/vinorelbine
Chakravarthy21
38
IIA-IIIB
Neoadjuvant CRT > surgery
46.8 Gy
Feyerabend22
25
Formenti24
44
Inoperable recurrence/M0-1 IIB-IIIB
Formenti23
35
T3/T4/unresectable
Genet25
66
Inflammatory (M0)
Kao26
16
IIIB-IIIC
Definitive CRT þ hyperthermia Neoadjuvant CRT > surgery Neoadjuvant CRT > surgery Neoadjuvant CRT > surgery CRT surgery (81%)
Karasawa13
35
IIIB-IV/recurrent
Definitive CRT
Karasawa14
39
T4/M0-1
Definitive CRT
IIB-IIIB
Neoadjuvant CRT > surgery
Adams
18
Alvarado-Miranda12
Shanta27
Patients
Concurrent Chemotherapy
1117
a
Paclitaxel
Response Pathologic
Clinical
Toxicity
Local Control
23% CR, 11% PR 30% CR
NR
NR
NR
NR
Acute: 22.4% grade 3 skin Acute: 14% grade 3 skin Late: 8% grade 3 skin Acute: 3.3% grade 3, 3.3% grade 4 skin 2 flap revisions Acute: 16% grade 3 skin Acute: 7% grade 3 skin 14% postoperative complication Acute: 25.7% grade 2þ skin 1 late skin toxicity 6 rib fractures Acute: 43% grade 3, 6% grade 4 Late: 13% grade 3 skin, 6% grade 3 lymphedema, 6% grade 3 joint Acute: 3% grade 3/4 skin, 3% grade 3 pneumonitis Acute: 23% grade 3 skin, 3% grade 3 pneumonitis NR
1 local recurrence 97% LC 90% LRC at 5 years NR
27% CR
20% CR 34% PR
Paclitaxel
34% CR
18% CR
Mean 49.4 Gy (36-70 Gy)b 45 Gy
Epirubicin/ifosfamide
NA
50 Gy
5-FU
45 Gyc þ 24-26 Gy boost Median 60 Gy (54-69 Gy)
5-FU/CDDP
Median 60 Gy (54-69 Gy) Median 60 Gy (59-66 Gy) 40 Gy
Paclitaxel
44% CR 36% PR 16% CR 18% 80% CR 11% PR PR 20% CR 14% 11% CR 60% PR PR 88% CR 88% CR
Paclitaxel vinorelbine
56% CR
NR
Docetaxel
NA
Docetaxel or paclitaxel CMF or CAF
NA
68% CR 28% PR 41% CR 53% PR NR
45% CR
5 mo median LC NR NR NR 83% LRC
NR 74% LC at 2 years 7% local failure (crude)
Abbreviations: CAF ¼ cyclophosphamide, doxorubicin, 5-fluorouracil; CDDP ¼ cisplatin; CMF ¼ cyclophosphamide, methotrexate, 5-fluorouracil; CR ¼ complete response; CRT ¼ chemoradiotherapy; 5-FU ¼ 5-fluorouracil; Gem ¼ gemcitabine; LC ¼ local control; LRC ¼ locoregional control; MMC ¼ mitomycin; NA ¼ not applicable; NR ¼ not reported; PR ¼ partial response. a All radiation delivered at 1.8-2 Gy/fraction unless indicated. b 32% treated at 1.2 Gy twice daily. c 1.5 Gy twice daily for 5 d every 4 wk.
Concurrent CRT for Inoperable Breast Cancer
Clinical Breast Cancer April 2015
Table 9 Selected Studies Using Concurrent Chemoradiotherapy on Intact Breast Tumors
Joseph N. Shaughnessy et al patients demonstrated an overall pCR rate with neoadjuvant chemotherapy of 13% to 22%, depending on how pCR was defined.28 Although a good surrogate marker for efficacy of treatment and a known positive prognosticator in those receiving neoadjuvant treatment, pCR rates can be influenced by factors including stage27 and tumor receptor status,29 again impairing direct comparison. Pathologic partial response has also been shown to be a positive prognostic factor.18,23 When reported, it varied between 11% and 18% in the CRT studies examined and was typically defined as a significant reduction in tumor with < 10 microscopic foci of residual disease. In the 2 studies with available pathologic data on patients receiving radiation alone for intact breast tumors, pCR rates were only 5% to 10%.2,9 These results, when taken together, show a higher rate of pathologic sterilization when using CRT compared with radiation alone. These results are not particularly surprising and would presumably translate into more sustained local tumor control, although no head-to-head comparisons exist. Because our series was mainly nonsurgical, response was judged clinically, with a clinical CR rate of 65% and a clinical PR rate of 35%. This was on the higher end of the range seen in other radiotherapy and CRT trials that reported clinical response data (Tables 8 and 9). Although this rate of clinical response was encouraging, especially given the advanced disease in our patient population, one can see from the aforementioned tables that clinical and pathologic response do not always go hand in hand. There can be significant discordance of up to 64% (clinical CR 80% vs. pathologic CR 16%), as seen in the study of Formenti et al.24 Additionally, the concept of clinical response is dependent on the assessor, with some degree of subjectivity at play. What was more encouraging was our 2-year LRFS of 73%. This was nearly identical to the 74% local control at 2 years found in a study by Karasawa et al, which used CRT as definitive therapy in a very similar patient population.14 Of the 5 local failures noted during our follow-up period, 3 were patients with recurrent disease treated with hyperfractionated repeated irradiation, which has been shown by others to be a risk factor for decreased tumor control.22 The 2-year OS of 80% in this high-risk population, with 55% of patients having metastatic disease at the time of treatment, is a testament to both the nature of breast cancer and the ever-improving systemic therapies, making long-lasting local therapy an essential component of care. A unique aspect of our study was the common use of hypofractionated radiotherapy. Although several of the radiation-alone studies used hypofractionation with success, with Arriagada et al4,5 using 2.5 Gy per fraction and Chargari et al treating with doses of 6.5 Gy per fraction, the CRT experiences were primarily with standard fractionation.7 The median total dose and dose per fraction in our study were 4500 cGy and 300 cGy, respectively. A total of 9 (45%) patients received this exact fractionation schedule as part of their treatment. There has been a recent trend toward hypofractionation in the adjuvant setting, with studies using dosing regimens similar to ours demonstrating equivalence to conventional fractionation in both recurrence rate and overall toxicity.30-32 A very similar fractionation schedule was used in the START A (UK Standardisation of Breast Radiotherapy Trial), in which a dose of 41.6 Gy was used at 3.2 Gy per fraction, with no increase in acute
or late toxicity at a median follow-up of 5 years.30 Just as in the START A and B trials, we were also comfortable using hypofractionation to treat nodal volumes when appropriate. Our treatment approach has evolved to prefer a hypofractionated approach because it allows for increased patient convenience with no observed detrimental effect on outcomes. Treatment was well tolerated in our patient population, with the majority of toxicity resolving with symptomatic treatment. Acute skin toxicity was the most common toxicity, which was consistent with other studies. Our rates may have been affected by the high number of patients with skin involvement at presentation, clouding proper assessment of treatment effect versus tumor involvement. Three patients with stage T4b or T4c disease did undergo eventual mastectomy for persistent ulceration > 3 months after treatment and were scored as having grade 4 toxicities. All 3 patients had uneventful postoperative courses and remained locoregionally disease free at last follow-up. Other larger neoadjuvant studies have reported higher rates of postoperative complications of up to 14%.24 If it is determined that a patient would benefit from surgery after treatment, we believe that the downstaging and long-term tumor control afforded by CRT outweigh the relatively low risk of postoperative complications. Pneumonitis, rib fracture, and lymphedema have been observed at acceptable rates in other larger studies but were not noted in our series. As more patients are treated with this approach and longer term follow-up accrues, additional toxicity may occur. Although cosmesis is not typically of primary concern in this specific population, the phase III ARCOSEIN trial looked at sequential versus concurrent chemotherapy and radiotherapy in the adjuvant setting after breast-conserving surgery and found no different in patient overall satisfaction with cosmetic outcome.16
Conclusion Patients treated with concurrent CRT in our series experienced marked tumor regression, with durable local disease control and acceptable treatment-related toxicity. Treatment did not preclude surgical resection if deemed necessary or potentially advantageous. Hypofractionated regimens were also used in our series safely and effectively. CRT is a viable treatment approach in patients with metastatic or unresectable disease in whom long-term local control is desired.
Clinical Practice Points Most patients with breast cancer are diagnosed with early-stage
disease and are eligible for surgical resection. A minority of patients will present with locally advanced or
metastatic disease, or both, and may be poor operative candidates for a variety of reasons. These may include poor performance status, extensive local infiltration, or patient preference. These patients are seeing continued gains in survival through the advancement of systemic therapies, including both chemotherapy regimens and novel targeted agents. Radiotherapy can be used to palliate the symptoms of locoregional tumor burden in these patients with modest success. Certain chemotherapeutic agents have been used as radiosensitizers at a multitude of disease sites, with gains in local control.
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Concurrent CRT for Inoperable Breast Cancer CRT has been used in breast cancer in several settings, including
neoadjuvant, definitive, and adjuvant approaches. This study details our institutional experience using concurrent
CRT for definitive local control in inoperable breast cancer. We saw impressive results in local control, with a favorable toxicity profile. Furthermore, we demonstrated that using a hypofractionated approach in this setting is safe and effective.
Disclosure The authors have stated that they have no conflicts of interest.
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