Volume 90, Issue 1, Pages 30-35 (January 2009)

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Pulsed dose rate brachytherapy as the sole adjuvant radiotherapy after breast-conserving surgery of T1–T2 breast cancer: First long time results from a clinical study

Received 30 January 2007; received in revised form 21 December 2007; accepted 25 February 2008. published online 14 April 2008.

Abstract

Background and purpose

To evaluate the long time outcome with regard to local tumour control, cosmetic outcome and side effects of a short (5 days) accelerated interstitial brachytherapy treatment delivered to the surroundings of the operated sector.

Patients and methods

Between 1993 and 2003 we treated 50 women with early T1 and T2 breast cancer. Radical sector resection was performed and followed later with an interstitial pulsed dose rate (PDR) brachytherapy of 50Gy in 5 days. The treatment was centred on the tumour with a margin of 30mm. One patient was treated bilaterally. The patients were followed for a median of 86 (32–126) months.

Results

Ipsilateral breast cancer recurrence was seen in 3 patients (6%). Two of them occurred outside the treated volume. The 5- and 7-year rates of actuarial local control were 96% and 96%, respectively, overall survival 88% and 85%, disease free survival 88% and 88%, respectively. A dosimetrical analysis showed that the partial breast irradiation covered a median of 31% of the total breast volume. Fat necrosis was seen in 12% and local (moderate–strong) fibrosis in 26% of the patients. Independent cosmetic scoring showed good or excellent result in 56% of the patients.

Conclusions

Local outcome is favourable and very similar to other published studies of accelerated partial breast irradiation. Our long time cosmetic results are lower than other published results.

Keywords: Brachytherapy, Pulsed dose rate, Breast cancer, Accelerated partial breast irradiation, Cosmetics, Outcome, Radiotherapy

Article Outline

• Abstract

• Materials and methods

• Study cohort

• Surgery

• Pathology

• Implant technique

• Dosimetry

• Follow-up

• Statistical methods

• Results

• Treatment outcome

• Side effects

• Cosmetic evaluation

• Discussion

• Acknowledgment

• References

• Copyright

Reliable data is available on the benefit of adjuvant whole-breast radiotherapy (WBRT) following breast-conserving surgery (BCS) of early breast cancer. The addition of 45–50Gy external beam radiotherapy (EBRT) to surgery gives local recurrence reduction from 23% to 7% after 5 years [7]. Approximately 2/3rds of the local recurrences occur in the same quadrant as the primary tumour [20]. Pathology studies of mastectomy specimens from T1 to T2 cancers have shown that there is less than 9% residual invasive foci occurring at a greater distance than 3cm from the boundary of the tumour [13]. These facts form the theoretical background for accelerated partial breast irradiation (APBI). Adjuvant WBRT after BCS has shown the same survival as mastectomy alone [10]. The overall survival after 15 years is slightly improved by WBRT but this is counteracted by an increase in radiation induced cardio-vascular mortality [7]. Brachytherapy is one method of radiotherapy which can reduce radiation exposure to coronary vessels and reduce the incidence of this mortality later in life [16]. Adjuvant WBRT requires considerable time resources both from the perspective of the patients and the radiation department. It is also possible that an excessive waiting time for adjuvant WBRT might impair local control [14]. A large cohort study of 4694 Swedish women with breast cancer and BCS between 1981 and 1990 showed, surprisingly, that nearly 30% never received adjuvant WBRT [12]. APBI by brachytherapy shortens the total treatment time, may reduce the waiting time and makes it a useful alternative for adjuvant radiotherapy.

Up to now experience of APBI by brachytherapy has been reported for low dose rate (LDR), high dose rate (HDR) and pulsed dose rate (PDR) brachytherapy in several papers [22], [26], [40]. Pulsed dose rate (PDR) brachytherapy was introduced around 1990 as a substitute for LDR. Small pulses of HDR are given hourly or every second hour so that the overall dose rate and total dose will be equal to LDR schedules [6]. Although APBI by brachytherapy has been in clinical use for some time, we have not found any systematic studies with long time results with follow-up >5 years that have been published on adjuvant APBI and PDR fractionation.

The aim of this study was to investigate long-term outcome in patients with BCS treated with 50Gy PDR brachytherapy in a large volume implant with regard to local control, the cosmetic outcome and side effects. The results will also be compared to other series of LDR/HDR/PDR APBI brachytherapy and WBRT with EBRT as well.

Our hypothesis is that properly selected and performed APBI yields a similar local failure rate as WBRT used in clinical practice.

Materials and methods

Study cohort

Between December 1993 and March 2003 we included 50 women with BCS of early breast cancer in an open labelled uniform clinical study. One patient was included twice since she was diagnosed with bilateral breast cancers. Thus, this presentation is based on 51 treated breast cancers.

Inclusion criteria were unifocal invasive T1–T2 tumours irrespective of histopathology, N0–N1 (<4 involved lymph nodes), radical surgery with clear margins and no signs of multifocal invasive or in situ tumours.

Patient characteristics are shown in Table 1.

Table 1.

Clinical data for 50 patients treated for 51 breast cancers, one with bilateral cancers


Patient characteristics	n	%
Age: median=53years, range=40–72 years
⩽50years	17	33
>50years	34	67

TN-stage
T1N0	37	74
T1N1	4	8
T2N0	8	16
T2N1	2	4

Histology
Ductal	34	67
Ductal+limited DCIS	6	12
Lobular	3	6
Tubular/Tubuloductal	7	14
Ductal+Lobular	1	2

Tumour characteristics
Size: median=15mm, range=5–42mm
5–10mm	16	31
11–20	25	49
>20	10	20

Grade
Low	14	2
Medium	19	37
High	18	35

Receptor status
Positive	40	78
Negative	8	16
Unknown	3	6

Microscopical margin
⩽2mm but clear	17	33
3–10mm	18	35
>10mm	5	10
Clear, not measured	11	22

Adjuvant hormone treatment	10	20
Adjuvant chemotherapy	6	12

Surgery

Breast-conserving surgery (BCS) was performed as a sector resection [4]. Non-palpable tumours were marked with dye and a specimen radiography was performed to confirm complete resection. Palpable tumours were resected with an aim to establish a minimum margin of 10mm from the border of the tumour. The tissue defect in the breast was either left open or sutured as considered appropriate in each case by the surgeon, depending on the location of the tumour or the structure of the breast tissue.

Median time between diagnosis and surgery was 13 (0–42) days.

Pathology

The fresh specimen was examined and samples were taken for receptor analysis and DNA flow cytometry. The remaining specimen was fixed in 10% formaldehyde solution.

Adequate sections were stained with haematoxylin–eosin for analysis regarding histopathology and resection margin in all (6) directions.

Pathology reports were reviewed to document the resection margin of the fixed specimen.

Implant technique

We identified an “index point”, which was the point where the tumour centre was located, based on the information from mammography, preoperative and intraoperative palpation. The target was defined as the whole-breast thickness with a radius of at least 3cm around the index point.

Needle entrances were marked on the skin and a free hand insertion of the needles was performed. The needles were changed to plastic tubes. The number of planes depended on the breast thickness, usually 2–3 planes. We made a single plane implant of four catheters in only one case with an extremely peripheral breast cancer. We tried to implant the superficial needle about 1cm deep to the skin and the outer treatment position not closer than 5mm under the skin surface to avoid excessive skin dose. We had no limits in catheter placement and dwell positions close to the chest wall. The needles were arranged parallel with 15–20mm spacing in quadratic or triangular configurations according to the rules of the Paris system [24].

The interstitial implant was done perioperatively in 14 (28%) cases and post-operatively in 37 (72%) patients. The pathology report was finished within 2 days in the perioperative setting to confirm resection with clear margins, no multifocality and no need of EBRT to the lymph node areas before the brachytherapy treatment was started. The time between surgery and start of brachytherapy was always 2 days in the perioperative setting but for the whole material median time between surgery and brachytherapy was 35 (2–213) days. Two patients had adjuvant chemotherapy first and brachytherapy was started 154 and 213 days after surgery, respectively.

Four patients had adjuvant chemotherapy after the brachytherapy.

Ten patients had adjuvant hormonal treatment.

All patients received antibiotics during the implant period and the following 5 days.

Dosimetry

Two orthogonal films were taken of the implant. From these two orthogonal films a 3D volume of the implant geometry was reconstructed. The mean central dose (MCD) was the arithmetic mean of the local minimum doses in the dose points placed between the applicators in the central plane, placed according to the Paris system. The prescribed dose was the minimum target dose (MTD) and was defined as 85% of MCD. The dose distribution was optimised using standard geometrical optimisation on volume. The dose calculations were made in the Nucletron planning system (NPS, v.10 Nucletron International BV, Veenendaal, The Netherlands).

The treatment was given by pulsed irradiation and delivered with a microSelectron PDR (Nucletron International BV, Veenendaal, The Netherlands). The prescribed dose was 50Gy given in 12 pulses per day (interval 2h) over 5 days where the dose per pulse was 0.833Gy. The biologically effective dose (BED) for this fractionation, 56.8Gy for tumour (α/β=10) and 96.7Gy for late effects (α/β=2), is to be compared with other APBI fractionations [8], [29].

All treatments were reviewed and evaluated as recommended in ICRU 58 [15]. We could estimate the total breast volume from a CT study of the implant in 38 of the treated breasts. Unfortunately this CT study could not be used for skin dose calculations due to technical reasons. We then calculated the ratio between reference volume and the total breast volume to reveal what proportion of the breast that was irradiated to 50Gy by brachytherapy. A post-implant CT was not performed on the remaining 13 treated breasts for logistic reasons.

Follow-up

Clinical examinations were performed every 3 months during the first year followed by annual visits. Mammograms were obtained every 18 months. Fine needle biopsy was carried out if indicated. A cosmetic evaluation scored by both the patient (n=42) and independently by an oncology nurse was performed on all living patients (n=36) at last follow-up. Two digital photographs/views were obtained from 36 women for independent scoring. Photographs were not obtained in 14 patients because of death or logistic reasons. We used the four levels scale (poor, fair, good and excellent) for cosmetic scoring as used by other groups [28]. Local fibrosis and telangiectasia were classified as Grades 0, 1, 2, 3 from the LENT SOMA tables [1].

Statistical methods

Data from a clinical database were retrieved and analysed. Local tumour control, disease free survival and overall survival were analysed with a Kaplan–Meier technique.

We carried out a Wilcoxon rank sum test to see if there was any relation between the cosmetic outcome and dosimetric parameters. The relationship between occurrence of fat tissue necrosis and dosimetric quality parameters were analysed with Student’s t-test.

We performed a Spearman correlation between treated volume and grade of fibrosis.

All statistics were performed with the Stata 8.2 for software (Stata/SE 8.2 for Windows, StataCorp, College Station, TX).

Results

Treatment outcome

The median follow-up time was 86 months (32–126). No patient was lost for follow-up.

Three patients (6%) developed ipsilateral recurrence. One had a multicentric recurrence of lobular cancer after 18 months and she later developed distal metastases in the pleura after 50 months. The second patient had a local recurrence at 24 months. It was outside the treatment volume (6cm from the index point). The third patient had a recurrence at 112 months, located in another quadrant and with a different histopathology. Both the 5- and 7-year actuarial local control rates were 96%.

We also noted 2 patients (4%) with contralateral cancers; one case 12 years after previous irradiation of that breast and one case in a breast without previous cancer.

Seven patients (14%) developed distant metastases, which were combined with regional lymph node metastases in 2 patients. No isolated regional recurrence was seen. Both the actuarial disease free survival (DFS) rates at 5- and 7-years were 88%.

Actuarial overall survival rates (OS) at 5- and 7-years were 88% and 85%, respectively. Fig. 1 shows a graphical Kaplan–Meier summary of the material outcome.

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Fig. 1. Kaplan–Meier plot of local control (LC) (red), disease free survival (DFS) (black) and overall survival (OS) (blue).

A summary of the dosimetry findings is shown in Table 2.

Table 2.

Dosimetric and volumetric data for treated breast cancers


Variable	Median	Range
Breast volume (n=38) (cm3)	493	201–2861
Ref dose volume (n=51) (cm3)	160	53–300
Volume ratio (ref vol/breast vol)	0.31	0.07–0.63
150% Isodose volume (cm3)	31	17–95
200% Isodose volume (cm3)	12	6–28
DNR (=V150%/V100%)[30]	0.20	0.16–0.35
DHI (=(V100–V150)/V100[42]	0.80	0.65–0.84
UI[2]	1.83	1.46–2.16
QI[33]	2.14	1.36–3.16
Number of catheters	12	4–18
Instantaneous dose rate (Gy/h)	2.7	1.3–9.6
Pulse dose (Gy/2h) for 24h	0.83	0.83–0.83
Reference air kerma rate (mGy/h×m2)	2.09	1.15–5.20

Total reference air kerma (mGy)	0.64	0.38–0.96

Side effects

Early side effects (within 3 months) were usually mild. We noticed some local radio-dermatitis (RTOG/ESTRO Grades 1–2) in 20% of the patients, sometimes with secretion around the puncture sites. We noticed signs of infection in five patients, which was followed by a new antibiotic treatment. We saw moderate (Grade 2) and strong fibrosis (Grade 3) located in the treatment volume in 18% and 8% patients, respectively. Fat necrosis was seen in 10 patients (20%). Six of these patients (12%) had both symptoms and mammography findings [32] and four (8%) patients had only mammography findings. One of the symptomatic patient developed chronic pain Grade 2 in the breast and was subsequently treated by mastectomy. This patient also had a contralateral breast cancer and developed chronic pain also in that breast after post-operative external irradiation. Two patients had minor corrections by plastic surgery (release of fibrotic strings). One woman had undergone a reconstructive plastic surgery after resection of a central breast cancer and APBI.

Cosmetic evaluation

All living patients with preserved breasts made their own judgement of the cosmetic result at last follow-up. The result was scored as good or excellent in 51% of the patients. The oncology nurse scored the cosmetic outcome as good or excellent in 56% of the patients.

Thus, there was good agreement between these two methods of cosmetic evaluation.

The nurse and one of the authors (BJ) scored the occurrence of telangiectasia from photographs. We found no or minimal telangiectasia (Grades 0–1) in 78% of the cases and Grades 2 and 3 in 14% and 8%, respectively.

Discussion

Some initial published results show bad results of APBI with brachytherapy or electron beam irradiation [9], [27]. Proper patient selection and treatment technique has, however, proven to yield rather stable phase 2 study results, see Table 3, Table 4, Table 5.

Table 3.

Clinical data from 10 different accelerated partial breast irradiation studies using brachytherapy


Institution (ref)	n	T	NIC	L	N	Age (year)	RM
William Beaumont Hospital [5], [39], [40]	199	11 (1–29)	11	0	13	65 (40–90)	⩾2
German–Austrian[22], [31]	274	12 (2–30)	0	16	0	61 (39–85)	⩾2
Budapest NIO [25], [26], [39]	131	12 (1–20)	0	0	0	56 (38–78)	>0
Ochsner clinic [17]	51	14 (8–20)	>0	0	18	63 (40–77)	>0
Present study	51	15 (5–42)	0	8	12	53 (40–72)	>0
Massachusetts GH [19]	48	<20	0	NS	0	>18	>0
Virginia University [3]	44	12 (3–37)	2	7	18	62 (39–80)	>0
London Reg Ca Ctr [23]	39	16 (4–45)	0	0	15	59 (39–84)	>1
Tuft/Brown University [35], [37]	75	12 (3–40)	0	0	9	63 (38–84	>1
Kansas University [18]	25	10 (4–18)	0	12	0	74 (60–91)	>0

Number of included breast cancers (n).

Tumour size, median (range) in mm (T).

Percentage included non-invasive in situ cancer (NIC), lobular (L) and lymph node positive (N) cases are given as well as age (median and range) and required pathology margin (RM) in mm.

Not stated (NS).

Table 4.

Physical data from 10 different accelerated partial breast irradiation studies using brachytherapy


Institution (ref)	Dose rate/Dose	V	NC	M
William Beaumont Hospital [40]	LDR/50;HDR32/34	215 (98–407)	14 (8–23)	1-2
German–Austrian [22], [31]	HDR/32;PDR/50	62 (32–149)	12 (6–18)	⩾2
Budapest NIO[26], [39]	HDR/30/36	50 (11–82)	7 (3–10)	1–2
Ochsner clinic [40]	LDR/45;HDR/32	NS	15	>2
Present study	PDR/50	158 (53–300)	12 (4–18)	3a
Massachusetts GH [19], [40]	LDR/50/55/60	165 (76–204)	14 (10–16)	3
Virginia University [3], [39]	LDR/45;HDR/34	190 (71–510)	14 (12–20)	1–2
London Reg Ca Ctr [23]	HDR/37	30 (9.6–111)	7 (3–11)	0
Tuft/Brown University [36], [37]	HDR/34	176 (63–560)	16 (8–25)	2
Kansas University [18]	LDR/25	NS	NS	1

Dose rate and total dose Gy, LDR, low dose rate; HDR, high dose rate; PDR, pulsed dose rate.

Treated median volume (range) (V) in cm3.

Median number (range) of catheters (NC).

Applied safety margin (M) in centimetre.

Margin from index point. Not stated (NS).

Table 5.

Clinical outcome data from 10 different accelerated partial breast irradiation studies using brachytherapy


Institution (ref)	n	FU	TR	EF	CLC	EGC
William Beaumont Hospital [5]	199	68	1	1.5	1	99 (at 60m)
German–Austrian [22], [31]	274	32	0.7	0	0	94
Budapest NIO [26]	131	84/36	0.7	3.8	NS	85
Ochsner clinic [39], [40]	160	84	1.3	1.2	NS	75 (at 46m)
Present study	51	86	2	4	4	56
Massachusetts GH [19]	48	23	0	0	NS	92
Virginia University [3]	44	42	0	0	0	80
London Reg Ca Ctr [23], [39]	39	91	5	10	5	NS
Tuft/Brown University [37], [40]	75	73	3	3	NS	91
Kansas University [18], [40]	25	47	3	0	3	100

Study size (n).

Median Follow-up (FU) in months.

Percentage true, within treated volume, true recurrence (TR).

Percentage elsewhere failure (EF).

Contralateral cancer (CLC).

Excellent–good cosmetic outcome (EGC). Not stated (NS).

There is a risk that very strict selection might result in a treatment cohort with a very low natural risk of local recurrence. Factors correlating to risk of local recurrence are low age, lymph node involvement, high tumour grade, lobular histology, surrounding extensive cancer in situ, tumour diameter and lack of hormone receptors [7], [11], [20]. It is also likely that the extent of surgery may have an impact on the risk of local recurrence [38]. Sector resection has been used in this study and has been investigated in previous randomized studies. The 10-year local recurrence rate was 8.5% with 50Gy post-operative external beam radiotherapy in stage I breast cancer in one Swedish study [20]. We tried to have reasonable selection criteria in our study that can be compared to other published studies, see Table 1, Table 3. In addition, 40% of our study population also had a history of concomitant or previous contralateral breast cancer.

Our implant philosophy was somewhat different to that described by other authors who use clips to delineate the surgical cavity, which together with a margin of 1–2cm is considered as the main target. Our reason for not using the resection cavity as the target centre was that >60% of our fixed specimens had a resection margin of ⩽10mm implying that the tumour was not centred in the resection specimen or cavity. From the pathology studies by Holland et al. [13] it is assumed that the residual cancer cells are stochastically centred around the tumour. We used a 3cm margin around the imagined tumour centre to compensate for uncertainty of the tumour centring. Table 4 shows that treated volume is similar to the North American groups but larger than the European groups. Few authors report the proportion of the breast volume, which is treated with the reference dose. In a dose–volume analysis from the William Beaumont group on 8 patients with rather large total breast volumes, they treated 16–25% of the total volume [41]. Dosimetry data from our study demonstrate that we covered in median 31% (7–63) of the total breast volume.

Table 5 shows the treatment outcome from different institutions. Our ipsilateral recurrence rate of 2% (1 patient) within treatment volume and 4% (2 patients) outside treatment volume is similar to other studies with long time follow-up. Of our patients 82% were followed for more than 5 years.

The cosmetic scoring was lower than the reported by other groups, see Table 4. Cosmetic data on Swedish practice of surgery and external beam radiotherapy after stage I breast cancer at 36-month have been reported [21]. Independent observers scored 80% of the patients to be good to excellent. A randomized Canadian study on stages I and II cancers with post-operative WBRT and 15Gy iridium or electron boost was scored to have good to excellent cosmetic results after 3 years in 65% and 62% of the patients, respectively [34]. Our study was carried out with somewhat larger surgery (sector resection), the tissue defect was usually not closed and the treated volumes were rather large. This might influence the cosmetic outcome. All dose planning was done in the era before CT based planning which may have given the possibility to safely treating more limited volumes. In an attempt to find the explanation to the given cosmetic scoring we analysed the collected photographs. Surgical factors (volume reduction, deformation, scaring) explained 44% and brachytherapy factors (telangiectasia, sclerosis, fibrotic retraction) explained 19%. In 13% there was a combination of these factors. In 24% it was not possible to make a certain evaluation. We were not able to demonstrate any significant correlation between different dosimetric parameters concerning cosmetic scoring and fat necroses. We noted a borderline correlation (p=0.07) between dose homogeneity index (DHI)[42] and patient cosmetic scoring. This is in agreement with the data from the Tuft/Brown group who found that DHI, V150 and the number of dwell positions were significantly associated with long-term cosmetic outcome [37]. We found no correlation between grade of fibrosis and treated volume (r=−0.15, p=0.26).

The rate of asymptomatic fat tissue necroses (8% at 7 years) is similar to the data from the German–Austrian trial (4.7% at 3 years). Our rates of Grades 2–3 fibrosis (26%) and telangiectasia (22%) at 7 years are higher than the German–Austrian at 3 years (7.7% and 4.6%, respectively) [22].

In conclusion this study on PDR brachytherapy as adjuvant radiotherapy of 51 breast cancers showed, after median follow-up of 86 months, an ipsilateral recurrence rate of 2% (1 patient) within the treatment volume and 4% (2 patients) outside the treatment volume. The recurrence rate is well within the range achieved after external beam radiotherapy and similar as in other published studies on APBI. The treatment was well tolerated and is less time consuming and probably a less costly alternative to external beam irradiation.

Cosmetic outcome will probably be improved by more proper surgical technique and use of image guided CT based 3D planning, where the treatment volume may be more limited and the skin dose completely controlled.

Acknowledgements

The Weiderman donation, Svenssons memorial foundation and research committee of Örebro county council supported this work. The authors thank Kerstin Kruse R.N. for help with cosmetic evaluation and to Michael Carlberg M.Sc. for statistical calculations. Thanks are also due to Terence Kearey for proof reading and correction of the English document.

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a Department of Oncology, Örebro University Hospital and Örebro University, Sweden

b Department of Medical Physics, and, Örebro University Hospital and Örebro University, Sweden

c Department of Surgery, Örebro University Hospital and Örebro University, Örebro, Sweden

Corresponding author. Department of Oncology, Örebro University Hospital and Örebro University, SE-70185 Örebro, Sweden.

PII: S0167-8140(08)00134-5

doi:10.1016/j.radonc.2008.02.022

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