Ann Surg Oncol DOI 10.1245/s10434-014-3545-5
ORIGINAL ARTICLE – ENDOCRINE TUMORS
Anaplastic Thyroid Carcinoma: A 25-year Single-Institution Experience A. Mohebati, MD1, M. DiLorenzo, BA1, F. Palmer, BA1, S. G. Patel, MD1, D. Pfister, MD2, N. Lee, MD3, R. M. Tuttle, MD4, A. R. Shaha, MD1, J. P. Shah, MD1, and I. Ganly, MD, PhD1 Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY; 2Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY; 3Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY; 4Department of Endocrinology, Memorial Sloan-Kettering Cancer Center, New York, NY 1
ABSTRACT Background. Anaplastic thyroid carcinoma (ATC) is among the most aggressive solid tumors accounting for 1– 5 % of primary thyroid malignancies. In this retrospective review, we aim to evaluate the prognostic factors, treatment approaches, and outcomes of patients with ATC treated at a single institution. Materials and Methods. We retrospectively identified 95 patients with ATC from an institutional database between 1985 and 2010. A total of 83 patients with sufficient records were included in this study. Patient, tumor, and treatment characteristics were recorded. Disease-specific survival (DSS) was determined by the Kaplan–Meier method, and factors predictive of outcome were determined by univariate and multivariate analysis. Results. Of the 83 patients, 41 were male and 42 were female. The median age at presentation was 60 years (range 28–89 years) with a median survival of 8 months. The 1- and 2-year DSS were 33 and 23 %, respectively. On univariate analysis, age less than 60 years, clinically N0 neck, absence of clinical extrathyroidal extension (cETE), gross total resection, and multimodality treatment were statistically significant predictors of improved survival. On multivariate analysis, absence of cETE, multimodality
Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-3545-5) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 24 October 2013 I. Ganly, MD, PhD e-mail: [email protected]
therapy, and gross total resection were predictors of improved outcome. Conclusions. In patients with locoregional limited disease, multimodality treatment with gross total surgical resection and postoperative radiotherapy with or without chemotherapy offers the best local control and DSS.
Anaplastic thyroid carcinoma (ATC) is a rare variant of thyroid cancer accounting for 1–5 % of all thyroid cancers.1–3 The incidence of ATC has been reported to be decreasing in certain parts of the world.4 However, it is one of the most aggressive human solid tumors, accounting for up to 50 % of thyroid cancer mortality with a reported median survival of only 3–5 months.5–7 The global rate of ATC is reported as high as 7 % of thyroid cancers.5 ATC can arise in three ways: as the terminal differentiation of well-differentiated thyroid cancer, in the setting of goiter, or de novo. Although ATC is an aggressive disease, longterm survival has been reported in a small number of select patients. Given the rarity of this disease, the optimal management of ATC remains controversial. Understanding the behavior of the disease is essential in identifying the group of patients that would benefit from aggressive multimodality treatment. The aim of this study was to describe our experience in the management of ATC and to evaluate the prognostic factors that have an impact on outcome. METHODS Following institutional review board approval, a retrospective review of our institutional thyroid database was performed to identify patients with ATC managed by the head and neck service at Memorial Sloan Kettering Cancer
A. Mohebati et al.
Center (MSKCC) between 1985 and 2010. A total of 95 patients were identified, of whom 83 patients had sufficient data and follow-up for analysis. Patient, tumor, and treatment characteristics were recorded from medical records. Surgical resection was classified as either R0 resection (complete resection of the tumor with no microscopic residual disease), R1 resection (residual microscopic disease), and R2 resection (residual macroscopic disease). All pathologic specimens were reviewed at MSKCC department of pathology. Cancer-related status was captured according to the most recent follow-up visit or hospital stay. Cause of death was reported as ATC-related or unrelated. The overall survival (OS) and disease-specific survival (DSS) were calculated by the Kaplan–Meier method and factors predictive of outcome determined by univariate and multivariate analysis. Predictors of DSS were identified using the log-rank test and considered significant if the P \ .05.
TABLE 1 Treatment characteristics n (%) Treatment type No treatment
10 (12 %)
Chemo/RT
4 (5 %)
RT alone
3 (4 %)
Surgery?PORT
12 (14 %)
Surgery?PORT?chemo
38 (46 %)
Surgery?chemo
9 (11 %)
Treatment groups Other (no surgery, or surgery alone)
24 (29 %)
Surgery±PORT±CT Resection type
59 (71 %)
R0/1
28 (34 %)
R2/X
41 (49 %)
No surgery/treatment
14 (17 %)
RESULTS
1.0
0.8
Cum Survival
The demographic data for the 83 patients is presented in Supplementary Table 1. There were 41 males and 42 females with the median age at presentation 60 years (range 28–89 years). A total of 19 patients (23 %) had a prior history of thyroid cancer, and 63 patients had a history of a thyroid mass for more than 9 months. Also, 29 % of the patients presented with vocal cord paralysis. Supplementary Table 2 shows details of patients who had a prior history of thyroid cancer. Details were only available on 12 of these patients because of the retrospective nature of the study and the fact many patients had had prior surgery carried out at other institutions. Of these 12 patients, 5 patients had had lobectomy (n = 2) or subtotal thyroidectomy (n = 3) and 7 had had total thyroidectomy. There were 7 patients who had advanced stage T4a tumors and 8 who had more aggressive histologies with 2 patients with poorly differentiated, 5 with tall cell variant, and 1 with sclerosis and metaplasia. Median time to anaplastic thyroid cancer diagnosis was 5.1 years (range 1.1–41.3 years). Of the 83 patients included in the study, 47 had preoperative fine needle aspiration of the mass done. Only 10 of those were diagnosed as anaplastic thyroid cancer on cytology (Supplementary Table 3). At the time of diagnosis, 31 patients (41 %) had gross evidence of extrathyroid extension (ETE), 23 (28 %) had clinical evidence of nodal disease, and 20 (24 %) had evidence of distant metastasis. Treatment characteristics are shown in Table 1. A total of 59 patients (71 %) were treated with a combination of surgery and radiation therapy with or without chemotherapy. Also, 10 patients (12 %) were treated with surgery alone; of these all were recommended chemoradiation but
7 (8 %)
Surgery alone
0.6
0.4
1 Yr DSS: 33% 2 Yr DSS: 23%
0.2
0.0 .0
6.0
12.0
18.0
24.0
30.0
36.0
Time (months)
FIG. 1 DSS of anaplastic thyroid cancer patients treated at MSKCC (1985–2010)
none received this because of either patient refusal or death before commencement of treatment. There were 7 patients (8 %) who received radiation with or without chemotherapy. The dose of radiation varied from 600 to 7,000 cGy. The most commonly used chemotherapeutic agents were doxorubicin or platinum-based agents. Also, 7 patients (8 %) did not receive any treatment. Tracheostomy was performed in 20 patients (24 %) for impending airway compromise. The median survival in this cohort was 8 months. The median follow-up was 6.5 months (range 1–198 months). The 1-year DSS was 33 % (Fig. 1). The median survival of the 7 patients who did not receive any therapy was 2 months, and no patient was alive at 1 year. On univariate
Anaplastic Thyroid Carcinoma
DISCUSSION
TABLE 2 Factors predictive of DSS on univariate analysis Characteristic
n (%)
1-year DSS p value (%)
Age (median, 60 years)
.012*
B60 years
28 (35) 52
[ 60 years
55 (65) 24
Gender
.622
Male
41 (49) 34
Female
42 (51) 32
History of thyroid cancer No Yes
.086 64 (77) 38 19 (23) 13.40
History of thyroid mass
.07
[9 months
63 (76) 25
\9 months
17 (20) 57
Unknown
3 (4)
67
M stage
.225
M0
58 (70) 37
M1
20 (24) 21
Mx
5 (6)
40
Gross ETE
.001*
No
38 (46) 46
Yes
34 (41) 10
Unknown
11 (13) 54
cN? No
.02* 47 (56) 41
Yes
23 (28) 15
Unknown
13 (16) 36 \.001*
Treatment groups Other (no surgery, or surgery alone) 24 (29) Surgery ? (multimodality)
6
59 (71) 42 \.001*
Resection type R0/1
28 (34) 54
R2/X
41 (49) 28
No surgery/treatment
14 (17)
8
* Statistically significant
analysis, age equal or less than 60 years, absence of gross ETE, absence of clinical nodal disease, multimodality therapy, and an R0/R1 resection were statistically significant predictors of improved outcome (Table 2). On multivariate analysis, absence of gross ETE (Fig. 2a), R0/ R1 resection (Fig. 2b), and multimodality treatment (Fig. 2c) were predictors of improved outcome (Table 3). Patients without gross ETE were 3 times less likely to die of disease compared with those with gross ETE (p = .002), patients with an R0/R1 resection were 2 times less likely to die compared with those with an R2/RX resection (p = .037), and patients treated with multimodality therapy were 3 times less likely to die (p = .013).
ATC usually presents as a rapidly enlarging neck mass causing hoarseness, dysphagia, and difficulty breathing. At presentation, the airway (larynx or trachea) and esophagus are often involved and surgical resection may not be possible. If identified early, surgery may be possible, the aim of which is to control the central compartment to prevent death by asphyxiation. Single-treatment modality is ineffective in the management of ATC. The incidence of ATC is reported to be higher in females and the elderly. In a prospective cohort of 5,583 cases of thyroid carcinoma, 70 % of the patients with ATC were female and 67 % were older than 70 years of age.8 In our cohort, there were no gender differences, but 65 % of the patients were older than 60 years of age. History of goiter has been associated with ATC.8,9 However, we found it difficult to identify the true incidence of goiter in our group of patients. Also, 63 patients had a history of a thyroid mass for more than 9 months, and 23 % of the patients had a history of thyroid cancer. This is similar to other reports that up to 50 % of patients with ATC have a concurrent or previous history of differentiated thyroid cancer.6,10–13 Of the 12 patients for whom details of prior thyroid cancer were available, we saw some interesting observations, notably that 7 (58 %) had advanced stage T4 tumors and 9 (75 %) had more aggressive pathologies (2 patients with poorly differentiated, 5 with tall cell variant, and 1 with sclerosis and metaplasia). This data suggests that patients with advanced stage primary tumors with aggressive histology are at risk of anaplastic thyroid cancer. On univariate analysis, we found that age less than 60 years, absence of gross ETE, multimodality therapy including surgical resection, and R0/R1 resection to be statistically significant predictors of improved survival. However, on multivariate analysis, absence of gross ETE, multimodality therapy, and gross total resection (R0/R1) were the only significant predictors of improved outcome. Similar predictors of outcome have been reported in the literature.4,14,15 In a report of clinical studies of 1,771 patients, variables associated with survival in some series included age, tumor size, extent of surgery, higher dose radiotherapy, absence of distant metastases at presentation, coexistence of differentiated thyroid cancer, and multimodality therapy.4 Sugitani et al.16 reported that the presence of acute symptoms, tumor [5 cm, distant metastasis, and WBC [10,000 mm3 were significant risk factors of worse survival from ATC in a multimodal analysis. They concluded that these prognostic factors (prognostic index) are viable means of selecting patients for aggressive multimodal therapy. In a study of 100 patients with ATC, multivariate analysis demonstrated that older age, high WBC, extrathyroidal invasion, distant metastasis at
A. Mohebati et al.
0.8
0.8
Cum Survival
(b)1.0
Cum Survival
(a) 1.0
0.6
0.4
0.6
0.4
No Residual Macroscopic Disease
No Extrathyroid Extension
0.2
0.2
0.0
1 Yr DSS No ETE: 46.0% ETE: 10.2% p=0.001
.0
Extrathyroid Extension
0.0
6.0
12.0
18.0
24.0
30.0
36.0
1 Yr DSS: R0/R1: 54.3% R2/Rx: 27.5% p=0.021
.0
6.0
Residual Macroscopic Disease
12.0
T ime (months)
0.8
0.8
Cum Survival
(d) 1.0
Cum Survival
(c) 1.0
0.6
0.4
Multimodal treatment
24.0
30.0
36.0
0.6
0.4
Surgery + ChemoRT
0.2
0.2
0.0
18.0
Time (months)
1 Yr DSS Multi: 42.4% Single: 6.0% p
ORIGINAL ARTICLE – ENDOCRINE TUMORS
Anaplastic Thyroid Carcinoma: A 25-year Single-Institution Experience A. Mohebati, MD1, M. DiLorenzo, BA1, F. Palmer, BA1, S. G. Patel, MD1, D. Pfister, MD2, N. Lee, MD3, R. M. Tuttle, MD4, A. R. Shaha, MD1, J. P. Shah, MD1, and I. Ganly, MD, PhD1 Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY; 2Department of Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY; 3Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY; 4Department of Endocrinology, Memorial Sloan-Kettering Cancer Center, New York, NY 1
ABSTRACT Background. Anaplastic thyroid carcinoma (ATC) is among the most aggressive solid tumors accounting for 1– 5 % of primary thyroid malignancies. In this retrospective review, we aim to evaluate the prognostic factors, treatment approaches, and outcomes of patients with ATC treated at a single institution. Materials and Methods. We retrospectively identified 95 patients with ATC from an institutional database between 1985 and 2010. A total of 83 patients with sufficient records were included in this study. Patient, tumor, and treatment characteristics were recorded. Disease-specific survival (DSS) was determined by the Kaplan–Meier method, and factors predictive of outcome were determined by univariate and multivariate analysis. Results. Of the 83 patients, 41 were male and 42 were female. The median age at presentation was 60 years (range 28–89 years) with a median survival of 8 months. The 1- and 2-year DSS were 33 and 23 %, respectively. On univariate analysis, age less than 60 years, clinically N0 neck, absence of clinical extrathyroidal extension (cETE), gross total resection, and multimodality treatment were statistically significant predictors of improved survival. On multivariate analysis, absence of cETE, multimodality
Electronic supplementary material The online version of this article (doi:10.1245/s10434-014-3545-5) contains supplementary material, which is available to authorized users. Ó Society of Surgical Oncology 2014 First Received: 24 October 2013 I. Ganly, MD, PhD e-mail: [email protected]
therapy, and gross total resection were predictors of improved outcome. Conclusions. In patients with locoregional limited disease, multimodality treatment with gross total surgical resection and postoperative radiotherapy with or without chemotherapy offers the best local control and DSS.
Anaplastic thyroid carcinoma (ATC) is a rare variant of thyroid cancer accounting for 1–5 % of all thyroid cancers.1–3 The incidence of ATC has been reported to be decreasing in certain parts of the world.4 However, it is one of the most aggressive human solid tumors, accounting for up to 50 % of thyroid cancer mortality with a reported median survival of only 3–5 months.5–7 The global rate of ATC is reported as high as 7 % of thyroid cancers.5 ATC can arise in three ways: as the terminal differentiation of well-differentiated thyroid cancer, in the setting of goiter, or de novo. Although ATC is an aggressive disease, longterm survival has been reported in a small number of select patients. Given the rarity of this disease, the optimal management of ATC remains controversial. Understanding the behavior of the disease is essential in identifying the group of patients that would benefit from aggressive multimodality treatment. The aim of this study was to describe our experience in the management of ATC and to evaluate the prognostic factors that have an impact on outcome. METHODS Following institutional review board approval, a retrospective review of our institutional thyroid database was performed to identify patients with ATC managed by the head and neck service at Memorial Sloan Kettering Cancer
A. Mohebati et al.
Center (MSKCC) between 1985 and 2010. A total of 95 patients were identified, of whom 83 patients had sufficient data and follow-up for analysis. Patient, tumor, and treatment characteristics were recorded from medical records. Surgical resection was classified as either R0 resection (complete resection of the tumor with no microscopic residual disease), R1 resection (residual microscopic disease), and R2 resection (residual macroscopic disease). All pathologic specimens were reviewed at MSKCC department of pathology. Cancer-related status was captured according to the most recent follow-up visit or hospital stay. Cause of death was reported as ATC-related or unrelated. The overall survival (OS) and disease-specific survival (DSS) were calculated by the Kaplan–Meier method and factors predictive of outcome determined by univariate and multivariate analysis. Predictors of DSS were identified using the log-rank test and considered significant if the P \ .05.
TABLE 1 Treatment characteristics n (%) Treatment type No treatment
10 (12 %)
Chemo/RT
4 (5 %)
RT alone
3 (4 %)
Surgery?PORT
12 (14 %)
Surgery?PORT?chemo
38 (46 %)
Surgery?chemo
9 (11 %)
Treatment groups Other (no surgery, or surgery alone)
24 (29 %)
Surgery±PORT±CT Resection type
59 (71 %)
R0/1
28 (34 %)
R2/X
41 (49 %)
No surgery/treatment
14 (17 %)
RESULTS
1.0
0.8
Cum Survival
The demographic data for the 83 patients is presented in Supplementary Table 1. There were 41 males and 42 females with the median age at presentation 60 years (range 28–89 years). A total of 19 patients (23 %) had a prior history of thyroid cancer, and 63 patients had a history of a thyroid mass for more than 9 months. Also, 29 % of the patients presented with vocal cord paralysis. Supplementary Table 2 shows details of patients who had a prior history of thyroid cancer. Details were only available on 12 of these patients because of the retrospective nature of the study and the fact many patients had had prior surgery carried out at other institutions. Of these 12 patients, 5 patients had had lobectomy (n = 2) or subtotal thyroidectomy (n = 3) and 7 had had total thyroidectomy. There were 7 patients who had advanced stage T4a tumors and 8 who had more aggressive histologies with 2 patients with poorly differentiated, 5 with tall cell variant, and 1 with sclerosis and metaplasia. Median time to anaplastic thyroid cancer diagnosis was 5.1 years (range 1.1–41.3 years). Of the 83 patients included in the study, 47 had preoperative fine needle aspiration of the mass done. Only 10 of those were diagnosed as anaplastic thyroid cancer on cytology (Supplementary Table 3). At the time of diagnosis, 31 patients (41 %) had gross evidence of extrathyroid extension (ETE), 23 (28 %) had clinical evidence of nodal disease, and 20 (24 %) had evidence of distant metastasis. Treatment characteristics are shown in Table 1. A total of 59 patients (71 %) were treated with a combination of surgery and radiation therapy with or without chemotherapy. Also, 10 patients (12 %) were treated with surgery alone; of these all were recommended chemoradiation but
7 (8 %)
Surgery alone
0.6
0.4
1 Yr DSS: 33% 2 Yr DSS: 23%
0.2
0.0 .0
6.0
12.0
18.0
24.0
30.0
36.0
Time (months)
FIG. 1 DSS of anaplastic thyroid cancer patients treated at MSKCC (1985–2010)
none received this because of either patient refusal or death before commencement of treatment. There were 7 patients (8 %) who received radiation with or without chemotherapy. The dose of radiation varied from 600 to 7,000 cGy. The most commonly used chemotherapeutic agents were doxorubicin or platinum-based agents. Also, 7 patients (8 %) did not receive any treatment. Tracheostomy was performed in 20 patients (24 %) for impending airway compromise. The median survival in this cohort was 8 months. The median follow-up was 6.5 months (range 1–198 months). The 1-year DSS was 33 % (Fig. 1). The median survival of the 7 patients who did not receive any therapy was 2 months, and no patient was alive at 1 year. On univariate
Anaplastic Thyroid Carcinoma
DISCUSSION
TABLE 2 Factors predictive of DSS on univariate analysis Characteristic
n (%)
1-year DSS p value (%)
Age (median, 60 years)
.012*
B60 years
28 (35) 52
[ 60 years
55 (65) 24
Gender
.622
Male
41 (49) 34
Female
42 (51) 32
History of thyroid cancer No Yes
.086 64 (77) 38 19 (23) 13.40
History of thyroid mass
.07
[9 months
63 (76) 25
\9 months
17 (20) 57
Unknown
3 (4)
67
M stage
.225
M0
58 (70) 37
M1
20 (24) 21
Mx
5 (6)
40
Gross ETE
.001*
No
38 (46) 46
Yes
34 (41) 10
Unknown
11 (13) 54
cN? No
.02* 47 (56) 41
Yes
23 (28) 15
Unknown
13 (16) 36 \.001*
Treatment groups Other (no surgery, or surgery alone) 24 (29) Surgery ? (multimodality)
6
59 (71) 42 \.001*
Resection type R0/1
28 (34) 54
R2/X
41 (49) 28
No surgery/treatment
14 (17)
8
* Statistically significant
analysis, age equal or less than 60 years, absence of gross ETE, absence of clinical nodal disease, multimodality therapy, and an R0/R1 resection were statistically significant predictors of improved outcome (Table 2). On multivariate analysis, absence of gross ETE (Fig. 2a), R0/ R1 resection (Fig. 2b), and multimodality treatment (Fig. 2c) were predictors of improved outcome (Table 3). Patients without gross ETE were 3 times less likely to die of disease compared with those with gross ETE (p = .002), patients with an R0/R1 resection were 2 times less likely to die compared with those with an R2/RX resection (p = .037), and patients treated with multimodality therapy were 3 times less likely to die (p = .013).
ATC usually presents as a rapidly enlarging neck mass causing hoarseness, dysphagia, and difficulty breathing. At presentation, the airway (larynx or trachea) and esophagus are often involved and surgical resection may not be possible. If identified early, surgery may be possible, the aim of which is to control the central compartment to prevent death by asphyxiation. Single-treatment modality is ineffective in the management of ATC. The incidence of ATC is reported to be higher in females and the elderly. In a prospective cohort of 5,583 cases of thyroid carcinoma, 70 % of the patients with ATC were female and 67 % were older than 70 years of age.8 In our cohort, there were no gender differences, but 65 % of the patients were older than 60 years of age. History of goiter has been associated with ATC.8,9 However, we found it difficult to identify the true incidence of goiter in our group of patients. Also, 63 patients had a history of a thyroid mass for more than 9 months, and 23 % of the patients had a history of thyroid cancer. This is similar to other reports that up to 50 % of patients with ATC have a concurrent or previous history of differentiated thyroid cancer.6,10–13 Of the 12 patients for whom details of prior thyroid cancer were available, we saw some interesting observations, notably that 7 (58 %) had advanced stage T4 tumors and 9 (75 %) had more aggressive pathologies (2 patients with poorly differentiated, 5 with tall cell variant, and 1 with sclerosis and metaplasia). This data suggests that patients with advanced stage primary tumors with aggressive histology are at risk of anaplastic thyroid cancer. On univariate analysis, we found that age less than 60 years, absence of gross ETE, multimodality therapy including surgical resection, and R0/R1 resection to be statistically significant predictors of improved survival. However, on multivariate analysis, absence of gross ETE, multimodality therapy, and gross total resection (R0/R1) were the only significant predictors of improved outcome. Similar predictors of outcome have been reported in the literature.4,14,15 In a report of clinical studies of 1,771 patients, variables associated with survival in some series included age, tumor size, extent of surgery, higher dose radiotherapy, absence of distant metastases at presentation, coexistence of differentiated thyroid cancer, and multimodality therapy.4 Sugitani et al.16 reported that the presence of acute symptoms, tumor [5 cm, distant metastasis, and WBC [10,000 mm3 were significant risk factors of worse survival from ATC in a multimodal analysis. They concluded that these prognostic factors (prognostic index) are viable means of selecting patients for aggressive multimodal therapy. In a study of 100 patients with ATC, multivariate analysis demonstrated that older age, high WBC, extrathyroidal invasion, distant metastasis at
A. Mohebati et al.
0.8
0.8
Cum Survival
(b)1.0
Cum Survival
(a) 1.0
0.6
0.4
0.6
0.4
No Residual Macroscopic Disease
No Extrathyroid Extension
0.2
0.2
0.0
1 Yr DSS No ETE: 46.0% ETE: 10.2% p=0.001
.0
Extrathyroid Extension
0.0
6.0
12.0
18.0
24.0
30.0
36.0
1 Yr DSS: R0/R1: 54.3% R2/Rx: 27.5% p=0.021
.0
6.0
Residual Macroscopic Disease
12.0
T ime (months)
0.8
0.8
Cum Survival
(d) 1.0
Cum Survival
(c) 1.0
0.6
0.4
Multimodal treatment
24.0
30.0
36.0
0.6
0.4
Surgery + ChemoRT
0.2
0.2
0.0
18.0
Time (months)
1 Yr DSS Multi: 42.4% Single: 6.0% p
