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Interstitial brachytherapy alone after breast conserving surgery: Interim results of a German-Austrian multicenter phase II trial
Brachytherapy 3 (2004) 115–119
Interstitial brachytherapy alone after breast conserving surgery: Interim results of a German-Austrian multicenter phase II trial Vratislav Strnad1,*, Oliver Ott1, Richard Po¨tter2, Guido Hildebrandt3, Josef Hammer4, Alexandra Resch2, Michael Lotter1, Sven Ackermann5, Matthias W. Beckmann5, Rolf Sauer1 1
Department of Radiation Oncology, Erlangen-Nu¨rnberg University, Erlangen, Germany Department of Radiation Oncology and Radiobiology, Vienna University, Vienna, Austria 3 Department of Radiation Oncology, Leipzig University, Leipzig, Germany 4 Department of Radiation Oncology, Barmherzige Schwestern Hospital, Linz, Austria 5 Department of Obstetrics and Gynecology, Erlangen-Nu¨rnberg University, Erlangen, Germany 2
ABSTRACT
PURPOSE: To evaluate the value of interstitial brachytherapy (iBT) alone in the treatment of lowrisk breast cancer patients with regard to local control, side effects, and cosmesis. METHODS AND MATERIALS: From November 2000 to January 2004, 176 patients with lowrisk breast cancer were treated with iBT only. Patients were eligible for entering the study if: the tumor size was ⬍3 cm; resection margins were clear by at least 2 mm; there were no lymph node metastases or only one micrometastasis (pNo, pNmi); age was ⬎35 years; steroid hormone receptor was positive; and histologic grade was 1 or 2. Seventy-five percent of patients received pulsed-dose-rate brachytherapy (Dref ⫽ 50 Gy); 25% of patients received high-dose-rate brachytherapy (Dref ⫽ 32.0 Gy). An interim analysis is presented for all patients after an interim follow-up of 12 months, and for half the patient population with an interim follow-up of 21 months. RESULTS: All patients remained disease-free on the date of analysis. A perioperative complication breast infection was recorded for 1/176 (0.6%) patients. Late toxicity i.e., hypersensation, hyperpigmentation, fibrosis, or teleangiectasia was observed in 1–12% of all patients. Grade I Fibrosis was registered in 7.6% (13/172) and grade II in 7.0% (12/172) of evaluable patients. Similarly, grade I teleangiectasia was observed in 4.7% (8/172), grade II in 0.6% (1/172), and grade III also in 0.6% (1/172) of evaluable patients. Excellent or good cosmetic results have been observed in 92–95% of patients. CONCLUSIONS: Brachytherapy as monotherapy in low-risk breast cancer patients after breastconserving surgery is an effective, precise treatment modality without perioperative morbidity, low acute, mild late toxicity, and yields good to excellent cosmetic results. 쑖 2004 American Brachytherapy Society. All rights reserved.
Keywords:
Breast cancer; Brachytherapy alone
Introduction Today, the value of external beam therapy after breast conserving surgery in patients with breast cancer is undisputed. Irradiation of the breast after breast conserving surgery
Received 8 June 2004; received in revised form 23 July 2004; accepted 1 August 2004. There is no financial or other interest in conjunction with the submitted manuscript among the authors. * Corresponding author. Department of Radiation Oncology, Universita¨t Erlangen-Nu¨rnberg, Universita¨tstr. 27, 91052 Erlangen, Germany. Tel.: ⫹49-9131-853-3419; fax: ⫹49-9131-853-9335. E-mail address: [email protected] (V. Strnad).
for invasive breast cancer is considered a therapeutic standard, particularly because of the significantly reduced rate of local recurrences. Apart from the advantages of breast conserving surgery and external beam therapy compared with surgery alone, external beam therapy also has disadvantages for the patient. Radiotherapy usually requires a therapy period of 5–6 weeks, where the patient is treated five times per week up to a total dose of approximately 50 Gy (25– 28 fractions; 1.8–2.0 Gy). This creates several problems, particularly for older patients in poor health or reduced mobility. Patients who work and patients with a daily journey of more than 50 km have to cope with substantial restrictions to their personal routines during external beam therapy. Interstitial brachytherapy as the sole radiation treatment increases
1538-4721/04/$ – see front matter 쑖 2004 American Brachytherapy Society. All rights reserved. doi:10.1016/j. br ach y .2 0 04 .0 8 .0 0 3
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Strnad et al. / Brachytherapy 3 (2004) 115–119
the quality of life, particularly for these patients. This report describes an interim analysis of a prospective multicenter phase II study using pulsed-dose-rate (PDR) or high-doserate (HDR) brachytherapy only in patients with low-risk breast cancer.
Methods and materials Patients From November 2000 to January 2004, 176 patients with low-risk breast cancer who had undergone breast conserving surgery were enrolled in an institutional ethics committee approved prospective multicenter phase-II protocol using interstitial PDR- or HDR- brachytherapy only after breast conserving surgery. In each participating institution (Erlangen, Vienna, Leipzig, Linz) all patients were treated similarly as described below. Criteria for eligibility were: stage I or II breast cancer; invasive breast carcinoma of any histology (DCIS only was not allowed); unifocal and unicentric breast cancer; no lymph invasion (L0) and no hemangiosis (V0); histopathologically confirmed lesions of ⭐ 3 cm diameter; pN0/pNmi (a minimum of nine lymph nodes in axillary clearance); no distant metastases; clear resection margins of at least 2 mm in any direction; steroid hormone receptor positive, and age ⭓ 35 years. Patient characteristics and distribution in regard to the brachytherapy schedule and systemic treatment shows that the majority of patients had tumors smaller than 2 cm and received adjuvant hormone therapy (Table 1). Surgery All patients received breast conserving surgery, including adaptation of surgical resection margins (closed cavity) and dissection of ipsilateral axillary lymph nodes. A clear resection margin of at least 1–2 mm was ensured in all patients. To assure 2 mm clear resection margins in all dimensions, the tissue specimen was dissected into microscopic tissue slices at 2 mm intervals. Subsequently, the surgical margins were measured in all directions in each tissue slice such that it was possible to define all eight surgical margins, for example, superior, inferior, medial, lateral, superficial, and deep [see (1) for details]. The surgical procedure was as follows: segmentectomy is defined as the removal of tumor with at least 1 cm of macroscopic healthy surrounding breast tissue, including the retromamillary parts of the draining ducts; quadrantectomy is the complete removal of the breast quadrant where the tumor is situated; and tumorectomy is defined only as a wide local excision with a margin of 1 cm adherent healthy tissue. The typical surgical procedure in this study comprises a skin incision over the tumor, after which a wide mobilization of the skin in all directions is performed. The breast tissue is then separated from the skin tissue and the tumor with the fascia of the pectoralis muscle is excised. The former position of the tumor is marked by
Table 1 Patient characteristics and distribution in regard to the brachytherapy schedule and systemic treatment
Follow up (months) Average Range Average age (years) Tumor diameter (mm) Average Range Tumor stage (%) pTmic pT1a pT1b pT1c pT2 Not available Grading (%) G1 G2 G3 Not available Resection margins (mm) Average Range Histology (%) Invasive ductal carcinoma Lobular carcinoma Tubular carcinoma Tubular-lobulary carcinoma Mucinous carcinoma Cribriforme carcinoma Ductal-lobulary carcinoma Squamous cell carcinoma Not available Surgery (%) Tumorectomy Quadrantectomy or segmentectomy Chemotherapy (%) EC ⫾ Hormone therapy FEC ⫹ Hormone therapy CMF ⫾ Hormone therapy Hormone therapy only (%) Tamoxifen Tamoxifen ⫹ Zoladex Arimidex No systemic therapy (%)
All patients (n ⫽ 176)
Subgroup (n ⫽ 88)
12 2–39 51
21 12–39 57
13 2–30
13 2–26
0.6 9.1 27.8 51.1 7.4 4.0
0 5.7 29.5 56.8 8.0 0
23.9 69.3 2.3 4.5
26.1 70.5 3.4 0
8 1–19
7 1–20
66.5 14.2 8.0 4.5 1.1 0.6 0.6 0.6 4.0
63.6 18.2 8.0 5.7 2.3 1.1 1.1 0 0
0.6 99.4
1.1 98.9
9.1 0.6 1.7
12.6 1.1 3.4
65.3 5.1 3.4 14.8
59.1 9.1 1.1 13.6
4–5 titanium clips placed mostly into the surface of the pectoralis muscle and the remaining breast tissue is reapproximated to cover the defect (“closed cavity”) and the breast is reconstructed with 1–2 sutures. The skin is then reapproximated with running stitches. Brachytherapy Implantation for all patients was done under general anesthesia, as it creates an absolutely pain-free treatment and also frees the physician from restrictions of implant form and size. The implant method was performed according the
Strnad et al. / Brachytherapy 3 (2004) 115–119
rules of the Paris System. After tumor bed localization, using CT or IBU (Integrated Brachytherapy Unit) according to the surgical clips, mammography, and ultrasound imaging under general anesthesia, hollow thin-wall stainless steel needles were inserted into the tumor bed and surrounding tissue (target volume) with at least 20 mm safety margins, if possible, in all directions. Hollow polyethylene afterloading catheters were introduced through these needles into the target volume and affixed with bottoms, followed by removal of the needles. The knowledge of the individual tumor-free resection margins was the basis for deciding the extent of safety margins for each implant, as the extent of safety margins for implant volume depends on the size of these tumor-free resection margins. In practice this means: 20 mm minus the minimum tumor-free resection margin (A) is the safety implant margin (B). The larger the tumor-free resection margin, the smaller will be the safety margin for the planning target volume (PTV): B ⫽ 20 ⫺ A (mm), but not smaller than 10 mm. Typically, the target volume was implanted with two or three planes, each plane consisting of three to eight catheters spaced 10–14 mm apart. Tubes were arranged in such a way that the lateral tubes were at least 20 mm outside the tumor bed/surgical clips. This method causes the prescription isodose to also be at least 20 mm outside the surgical clips and ensures that the tumor bed (the position of resection margins ⫽ the position of surgical clips) of the closed resection cavity is covered completely by the reference isodose. All lateral directions of the target volume were well encompassed by peripheral catheters, and in the directions toward the skin and thoracic wall, were encompassed by the base plane and the “surface” plane (2nd or 3rd plane). In some cases, when inevitable due to breast size, restrictions in implant thickness were made in the direction toward the chest wall and skin. For such cases the safety margins of the PTV were redefined to at least 5–7 mm below the skin surface. Irradiation was done by an afterloading device (microSelectron PDR or HDR; Nucletron Corp., Veneendaal, The Netherlands) with an 192Ir source, at a source strength (air-kerma rate, Ka.100) for PDR-brachytherapy within a range of 1.2 mGy.m2/H ⬍ Ka.100 ⬍ 4.8 mGy.m2/H and for the HDR-brachytherapy within a range of 15 mGy.m2/H ⬍ Ka.100 ⬍ 45 mGy.m2/H. The dose calculation was performed by the Plato Brachytherapy Planning System (Nucletron Corp., Veenendaal, The Netherlands), using geometrical optimization. For PDR-brachytherapy, a dose per pulse with a median value of 0.60 Gy (range, 0.4–1.0 Gy) up to a median total dose of 49.8 Gy (range, 49.0–51.3 Gy) was prescribed. The pulses were delivered for 24 h/d, with an interval of 1 hour between pulses. For HDR-brachytherapy, a dose of 4 Gy per fraction up to a total dose of 32 Gy was prescribed. For dose specification and prescription, rules similar to the Paris system were used. Thus, the dose per pulse of 0.6 Gy, or dose per fraction of 4.0 Gy, corresponded to the reference dose (Dref) in this study, which was prescribed at 85% of the mean central dose. The volume of the 85% isodose was about 60 cm3, with a 150% isodose volume of
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∼7–9 cm ; the dose homogeneity index (DHI) values were ∼0.8 (Table 2). According Wu et al. (2), DHI was defined as a fraction of the volume of the reference isodose receiving dose between 100% and 150% of the Dref; DHI ⫽ [V(Dref) ⫺ V(D150)] · V(Dref)⫺1. 3
Systemic therapy Adjuvant sequential chemotherapy and/or hormone therapy was allowed according to the local protocol of the treating center (Table 1). The time interval from the definitive breast surgery to the start of brachytherapy was about 60 days. If patients received chemotherapy, the brachytherapy was done either before the systemic treatment, or was given in the interval between the chemotherapy courses—in most cases between the first and second course of chemotherapy. Altogether, 20/176 women (11.4%) received systemic chemotherapy. Sixteen patients (9.1%) received three or six cycles of epirubicin and cyclophosphamide (EC) with or without hormone therapy, 1 patient had six cycles of 5fluorouracil, epirubicin and cyclophosphamide (FEC) and 3 other patients (1.7%) had six cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (for more details see Table 1).
Table 2 Brachytherapy parameters in all patients Parameters Interval of definitive surgery and brachytherapy (days) Average Range Number of implant tubes Average Range Implant volume (85% isodose) (cm3) Average Range Volume of 150% isodose (cm3) Average Range Dose homogeneity index Average Range Total dose (Gy) Average Range Dose per pulse (Gy/h/24h) Average Range Dose per fraction (Gy) Average Range
HDR brachytherapy (25% of all patients)
PDR brachytherapy (75% of all patients)
64 14–99
60 4–99
12 8–15
13 6–18
63.6 32.2–133.9
59.3 23.7–149.0
8.8 3.9–13.5
6.4 3.2–22.0
0.79 0.61–0.85
0.80 0.53–0.87
32 32–32
49.8 49.0–51.3
– –
0.60 0.40–1.00
4 4–4
– –
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Strnad et al. / Brachytherapy 3 (2004) 115–119
Statistical methods All patients were followed closely to analyze acute and late toxicity according to RTOG/EORTC and LENT-SOMA criteria, local control, and survival rates. All patients were included in the follow-up. The analysis was performed after a median follow-up of 12 months for the whole group of 176 patients and for a subgroup of 88 patients after a median follow-up of 21 months (12–39 months). Follow-up was calculated from the day of definitive surgery to the date of last follow-up. The primary endpoint of this analysis was the evaluation of treatment side effects. The secondary endpoint was the evaluation of the effect of brachytherapy on local control (local recurrence-free survival rate).
Results Treatment outcome At the time of analysis none of the patients, neither from the whole study group (176 patients, median follow-up 12 months) nor from the subpopulation (88 patients, median follow-up 21 months), developed ipsilateral or contralateral recurrence; likewise no patient showed clinical signs of distant metastases. Cosmetic results and side effects Only minimal acute side effects in a few patients, and mild late side effects, such as hypersensation, hyperpigmentation, fibrosis, or teleangiectasia, in 1–12% of all patients, were registered. Acute complications such as breast infection were recorded only in 1 patient (0.6%). The most frequent late effects were telangiectasia, grade I in 4.7% (8/172), grade II in 0.6% (1/172), and grade III also in 0.6% (1/ 172) of evaluable patients. Similarly, we observed fibrosis grade I in 7.6% (13/172) and grade II in 7.0% (12/172) of evaluable patients. Excellent or good cosmetic results have been observed in 92–95% of patients. Up to now it is not possible to find any differences in side effects according to the use of systemic therapy or to use of PDR- or HDRbrachytherapy. All acute and late side effects according to the RTOG/EORTC scoring, including cosmetic results are listed in Table 3.
Discussion The main advantage of brachytherapy as monotherapy in the organ conserving treatment of breast cancer is the potential to improve the quality of life for patients. We now have enough mature clinical data (3–9) demonstrating comparable long-term data—the same local control rates, survival rates, and minimal side effects compared with conventional whole breast radiotherapy (Table 4). Of course, proper patient selection and quality assurance are critical here. Inappropriate patient selection or suboptimal quality
Table 3 Side effects and cosmetic results from brachytherapy alone
Bleeding Hematoma Bacterial Implant infection Radiodermatitis Grade 1 Grade 2 Grade 3 Grade 4 Telangiectasia Grade 1 (⬍1 cm3) Grade 2 (1–4 cm3) Grade 3 (⬎4 cm3) Fibrosis Grade 1 Grade 2 Grade 3 Hypersensation Mild pigmentation Cosmesis (doctor’s opinion) Excellent Good Fair Poor Cosmesis (patient’s opinion) Excellent Good Fair Poor
All patients (n ⫽ 176)
Subgroup (n ⫽ 88)
0
0 0
1/176 (0.6%) 1/176 (0.6%)
1/88 (1.1%)
3/176 (1.7%) 2/176 (1.2 %) 0 0
4/88 (4.4%) 1/88 (1.1%) 0 0
8/172* (4.7 %) 1/172* (0.6%) 1/172* (0.6%) 13/172* 12/172* 0 2/172* 22/172*
(7.6%) (7.0%)
8/88 (9.1%) 1/88 (1.1%) 1/88 (1.1%) (11.4%) (4.5%)
(1.1%) (12.8%)
10/88 4/88 0 2/88 12/88
85/144* 50/144* 8/144* 1/144*
(59.0%) (34.7%) (5.6%) (0.7%)
47/88 34/88 6/88 1/88
(56.0%) (38.6%) (7.1%) (1.2%)
84/144* 48/144* 9/144* 3/144*
(58.3%) (33.3%) (6.3%) (2.1%)
45/88 28/88 8/88 3/88
(53.6%) (31.8%) (9.5%) (3.6%)
(2.3%) (13.6%)
* Some follow-up data were not available at the time of analysis.
assurance in the brachytherapy technique and/or target definition leads to unsatisfactory results. This is documented in some other trials (Table 5). The earlier data from this German-Austrian Trial were similar to the results presented in Table 4. We also believe that the long-term data and further analyses of our study will support the suggestion that brachytherapy alone is a reasonable approach for appropriately selected patients. The next step in this endeavor are the phase III trials, which begin this year in the US and Europe. Table 4 Results of selected large studies with proper patient selection and appropriate quality assurance Follow-up Recurrence Patients (n) (months) rate (%)
Institute (ref)
Technique
William Beaumont Hospital (8) Ochsner Clinic (5) National Institute of Oncology, Budapest (6–7) Virginia Commonwealth University (4) Present study
LDR/HDR
199
65
1.2
LDR/HDR HDR
160 45
84 70
2.5 4.4
LDR/HDR
59
50
5.1
PDR/HDR
176 69*
13 24
0 0
* Subpopulation of patients with 2-year follow-up.
Strnad et al. / Brachytherapy 3 (2004) 115–119 Table 5 Results of studies with inappropriate patient selection and/or suboptimal quality assurance in the brachytherapy technique and/or target definition Institute (ref.)
Follow-up Recurrence Technique Patients (n) (months) rate (%)
Christie Hospital (10, 11) EBI Guy’s Hospital (12) LDR London Regional HDR Cancer Center (13)
353 27 39
96 72 86
19.5 37 16.2
EBI ⫽ external beam irradiation.
Another question in this context is the appropriate brachytherapy technique. For partial breast irradiation, either the multi-catheter technique or the balloon system can be used. Each system has advantages and disadvantages. With the balloon system the advantages are: a short learning curve; treatment planning is simple and reliable in any center with a HDR remote-afterloader; good reproducibility; and only one puncture site. The main disadvantage of the balloon system is that despite some progress (14, 15) the target volume coverage compared with the multicatheter system is very limited in form and volume. With the multicatheter system, the main advantages are that the tumor parameters (inclusion criteria) are exactly known at the time of implantation and that the target volume coverage is not limited in form and volume. Further advantages of the multicatheter system are that it has very good reproducibility and the treatment planning is simple and reliable. Considered as possible disadvantages are more puncture sites (⬎10) and an individually-long learning curve. It is still not possible to say whether the balloon or the multicatheter system is better. The multicatheter system is very flexible and makes it possible to cover any form of target, but the balloon system is easy to handle. One has to await the results of the phase III studies to answer the above question. Conclusion Accelerated partial breast irradiation is a valuable therapy for appropriately selected low-risk breast cancer patients, but until results of phase III studies are published these patients should be treated in registered studies.
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References [1] Rosen PP. Pathologic examination of breast and lymph node specimens. In: Rosen PP, editor. Rosen’s breast pathology. Philadelphia: Lippincott, Williams & Wilkins; 2001. p. 931–990. [2] Wu A, Ulin K, Sternich ES. A dose homogeneity index for evaluating 192 Ir interstitial breast implants. Med Phys 1988;15:104–107. [3] Arthur D, Vicini F, Kuske RR, et al. Accelerated partial breast irradiation: An updated report from the American Brachytherapy Society. Brachytherapy 2002;1:184–190. [4] Arthur D, Koo D, Zwicker RD. Partial breast brachytherapy following lumpectomy: A low dose rate and high dose rate experience. Int J Radiat Oncol Biol Phys 2003;56:681–686. [5] King TA, Bolton JS, Kuske RR, et al. Long-term results of widefield brachytherapy as the sole method of radiation therapy after segmental mastectomy for T(is,1,2) breast cancer. Am J Surg 2000; 180:299–304. [6] Polgar C, Sulyok Z, Fodor J, et al. Sole brachytherapy of the tumor bed after conservative surgery for T1 breast cancer: Five-year results of a phase I-II study and initial findings of a randomized phase III trial. J Surg Oncol 2002;80:121–128. [7] Polgar C, Fodor J, Major T, et al. Radiotherapy confined to the tumor bed following breast conserving surgery current status, controversies, and future projects. Strahlenther Onkol 2002;178:597–606. [8] Vicini F, Arthur D, Polgar C, et al. Defining the efficacy of accelerated partial breast irradiation: The importance of proper patient selection, optimal quality assurance, and common sense. Int J Radiat Oncol Biol Phys 2003;57:1210–1213. [9] Vicini F, Arthur D, Wazer D. Inconsistency, perspective, double talk, and false virtue. Brachytherapy 2002;1:181–183. [10] Magee B, Young EASR. Patterns of breast relapse following breast conserving surgery and radiotherapy. Br J Cancer 1998;78(Suppl. 2):24. [11] Ribiero GG, Dunn G, Swindell R, et al. Conservation of the breast using two different radiotherapy techniques: Interim report of a clinical trial. Clin Oncol 1993;5:278–283. [12] Fentiman IS, Poole C, Tong D, et al. Inadequacy of iridium implant as sole radiation treatment for operable breast cancer. Eur J Cancer 1996;32A:608–611. [13] Perera F, Yu E, Engel J, et al. Patterns of breast recurrence in a pilot study of brachytherapy confined to the lumpectomy site for early breast cancer with six years’ minimum follow-up. Int J Radiat Oncol Biol Phys 2003;57:1239–1246. [14] Keisch M, Vicini F, Kuske RR, et al. Initial clinical experience with the MammoSite breast brachytherapy applicator in women with earlystage breast cancer treated with breast-conserving therapy. Int J Radiat Oncol Biol Phys 2003;55:289–293. [15] Astrahan MA, Jozsef G, Streeter OE. Optimization of MammoSite therapy. Int J Radiat Oncol Biol Phys 2004;58:220–232.
Interstitial brachytherapy alone after breast conserving surgery: Interim results of a German-Austrian multicenter phase II trial Vratislav Strnad1,*, Oliver Ott1, Richard Po¨tter2, Guido Hildebrandt3, Josef Hammer4, Alexandra Resch2, Michael Lotter1, Sven Ackermann5, Matthias W. Beckmann5, Rolf Sauer1 1
Department of Radiation Oncology, Erlangen-Nu¨rnberg University, Erlangen, Germany Department of Radiation Oncology and Radiobiology, Vienna University, Vienna, Austria 3 Department of Radiation Oncology, Leipzig University, Leipzig, Germany 4 Department of Radiation Oncology, Barmherzige Schwestern Hospital, Linz, Austria 5 Department of Obstetrics and Gynecology, Erlangen-Nu¨rnberg University, Erlangen, Germany 2
ABSTRACT
PURPOSE: To evaluate the value of interstitial brachytherapy (iBT) alone in the treatment of lowrisk breast cancer patients with regard to local control, side effects, and cosmesis. METHODS AND MATERIALS: From November 2000 to January 2004, 176 patients with lowrisk breast cancer were treated with iBT only. Patients were eligible for entering the study if: the tumor size was ⬍3 cm; resection margins were clear by at least 2 mm; there were no lymph node metastases or only one micrometastasis (pNo, pNmi); age was ⬎35 years; steroid hormone receptor was positive; and histologic grade was 1 or 2. Seventy-five percent of patients received pulsed-dose-rate brachytherapy (Dref ⫽ 50 Gy); 25% of patients received high-dose-rate brachytherapy (Dref ⫽ 32.0 Gy). An interim analysis is presented for all patients after an interim follow-up of 12 months, and for half the patient population with an interim follow-up of 21 months. RESULTS: All patients remained disease-free on the date of analysis. A perioperative complication breast infection was recorded for 1/176 (0.6%) patients. Late toxicity i.e., hypersensation, hyperpigmentation, fibrosis, or teleangiectasia was observed in 1–12% of all patients. Grade I Fibrosis was registered in 7.6% (13/172) and grade II in 7.0% (12/172) of evaluable patients. Similarly, grade I teleangiectasia was observed in 4.7% (8/172), grade II in 0.6% (1/172), and grade III also in 0.6% (1/172) of evaluable patients. Excellent or good cosmetic results have been observed in 92–95% of patients. CONCLUSIONS: Brachytherapy as monotherapy in low-risk breast cancer patients after breastconserving surgery is an effective, precise treatment modality without perioperative morbidity, low acute, mild late toxicity, and yields good to excellent cosmetic results. 쑖 2004 American Brachytherapy Society. All rights reserved.
Keywords:
Breast cancer; Brachytherapy alone
Introduction Today, the value of external beam therapy after breast conserving surgery in patients with breast cancer is undisputed. Irradiation of the breast after breast conserving surgery
Received 8 June 2004; received in revised form 23 July 2004; accepted 1 August 2004. There is no financial or other interest in conjunction with the submitted manuscript among the authors. * Corresponding author. Department of Radiation Oncology, Universita¨t Erlangen-Nu¨rnberg, Universita¨tstr. 27, 91052 Erlangen, Germany. Tel.: ⫹49-9131-853-3419; fax: ⫹49-9131-853-9335. E-mail address: [email protected] (V. Strnad).
for invasive breast cancer is considered a therapeutic standard, particularly because of the significantly reduced rate of local recurrences. Apart from the advantages of breast conserving surgery and external beam therapy compared with surgery alone, external beam therapy also has disadvantages for the patient. Radiotherapy usually requires a therapy period of 5–6 weeks, where the patient is treated five times per week up to a total dose of approximately 50 Gy (25– 28 fractions; 1.8–2.0 Gy). This creates several problems, particularly for older patients in poor health or reduced mobility. Patients who work and patients with a daily journey of more than 50 km have to cope with substantial restrictions to their personal routines during external beam therapy. Interstitial brachytherapy as the sole radiation treatment increases
1538-4721/04/$ – see front matter 쑖 2004 American Brachytherapy Society. All rights reserved. doi:10.1016/j. br ach y .2 0 04 .0 8 .0 0 3
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Strnad et al. / Brachytherapy 3 (2004) 115–119
the quality of life, particularly for these patients. This report describes an interim analysis of a prospective multicenter phase II study using pulsed-dose-rate (PDR) or high-doserate (HDR) brachytherapy only in patients with low-risk breast cancer.
Methods and materials Patients From November 2000 to January 2004, 176 patients with low-risk breast cancer who had undergone breast conserving surgery were enrolled in an institutional ethics committee approved prospective multicenter phase-II protocol using interstitial PDR- or HDR- brachytherapy only after breast conserving surgery. In each participating institution (Erlangen, Vienna, Leipzig, Linz) all patients were treated similarly as described below. Criteria for eligibility were: stage I or II breast cancer; invasive breast carcinoma of any histology (DCIS only was not allowed); unifocal and unicentric breast cancer; no lymph invasion (L0) and no hemangiosis (V0); histopathologically confirmed lesions of ⭐ 3 cm diameter; pN0/pNmi (a minimum of nine lymph nodes in axillary clearance); no distant metastases; clear resection margins of at least 2 mm in any direction; steroid hormone receptor positive, and age ⭓ 35 years. Patient characteristics and distribution in regard to the brachytherapy schedule and systemic treatment shows that the majority of patients had tumors smaller than 2 cm and received adjuvant hormone therapy (Table 1). Surgery All patients received breast conserving surgery, including adaptation of surgical resection margins (closed cavity) and dissection of ipsilateral axillary lymph nodes. A clear resection margin of at least 1–2 mm was ensured in all patients. To assure 2 mm clear resection margins in all dimensions, the tissue specimen was dissected into microscopic tissue slices at 2 mm intervals. Subsequently, the surgical margins were measured in all directions in each tissue slice such that it was possible to define all eight surgical margins, for example, superior, inferior, medial, lateral, superficial, and deep [see (1) for details]. The surgical procedure was as follows: segmentectomy is defined as the removal of tumor with at least 1 cm of macroscopic healthy surrounding breast tissue, including the retromamillary parts of the draining ducts; quadrantectomy is the complete removal of the breast quadrant where the tumor is situated; and tumorectomy is defined only as a wide local excision with a margin of 1 cm adherent healthy tissue. The typical surgical procedure in this study comprises a skin incision over the tumor, after which a wide mobilization of the skin in all directions is performed. The breast tissue is then separated from the skin tissue and the tumor with the fascia of the pectoralis muscle is excised. The former position of the tumor is marked by
Table 1 Patient characteristics and distribution in regard to the brachytherapy schedule and systemic treatment
Follow up (months) Average Range Average age (years) Tumor diameter (mm) Average Range Tumor stage (%) pTmic pT1a pT1b pT1c pT2 Not available Grading (%) G1 G2 G3 Not available Resection margins (mm) Average Range Histology (%) Invasive ductal carcinoma Lobular carcinoma Tubular carcinoma Tubular-lobulary carcinoma Mucinous carcinoma Cribriforme carcinoma Ductal-lobulary carcinoma Squamous cell carcinoma Not available Surgery (%) Tumorectomy Quadrantectomy or segmentectomy Chemotherapy (%) EC ⫾ Hormone therapy FEC ⫹ Hormone therapy CMF ⫾ Hormone therapy Hormone therapy only (%) Tamoxifen Tamoxifen ⫹ Zoladex Arimidex No systemic therapy (%)
All patients (n ⫽ 176)
Subgroup (n ⫽ 88)
12 2–39 51
21 12–39 57
13 2–30
13 2–26
0.6 9.1 27.8 51.1 7.4 4.0
0 5.7 29.5 56.8 8.0 0
23.9 69.3 2.3 4.5
26.1 70.5 3.4 0
8 1–19
7 1–20
66.5 14.2 8.0 4.5 1.1 0.6 0.6 0.6 4.0
63.6 18.2 8.0 5.7 2.3 1.1 1.1 0 0
0.6 99.4
1.1 98.9
9.1 0.6 1.7
12.6 1.1 3.4
65.3 5.1 3.4 14.8
59.1 9.1 1.1 13.6
4–5 titanium clips placed mostly into the surface of the pectoralis muscle and the remaining breast tissue is reapproximated to cover the defect (“closed cavity”) and the breast is reconstructed with 1–2 sutures. The skin is then reapproximated with running stitches. Brachytherapy Implantation for all patients was done under general anesthesia, as it creates an absolutely pain-free treatment and also frees the physician from restrictions of implant form and size. The implant method was performed according the
Strnad et al. / Brachytherapy 3 (2004) 115–119
rules of the Paris System. After tumor bed localization, using CT or IBU (Integrated Brachytherapy Unit) according to the surgical clips, mammography, and ultrasound imaging under general anesthesia, hollow thin-wall stainless steel needles were inserted into the tumor bed and surrounding tissue (target volume) with at least 20 mm safety margins, if possible, in all directions. Hollow polyethylene afterloading catheters were introduced through these needles into the target volume and affixed with bottoms, followed by removal of the needles. The knowledge of the individual tumor-free resection margins was the basis for deciding the extent of safety margins for each implant, as the extent of safety margins for implant volume depends on the size of these tumor-free resection margins. In practice this means: 20 mm minus the minimum tumor-free resection margin (A) is the safety implant margin (B). The larger the tumor-free resection margin, the smaller will be the safety margin for the planning target volume (PTV): B ⫽ 20 ⫺ A (mm), but not smaller than 10 mm. Typically, the target volume was implanted with two or three planes, each plane consisting of three to eight catheters spaced 10–14 mm apart. Tubes were arranged in such a way that the lateral tubes were at least 20 mm outside the tumor bed/surgical clips. This method causes the prescription isodose to also be at least 20 mm outside the surgical clips and ensures that the tumor bed (the position of resection margins ⫽ the position of surgical clips) of the closed resection cavity is covered completely by the reference isodose. All lateral directions of the target volume were well encompassed by peripheral catheters, and in the directions toward the skin and thoracic wall, were encompassed by the base plane and the “surface” plane (2nd or 3rd plane). In some cases, when inevitable due to breast size, restrictions in implant thickness were made in the direction toward the chest wall and skin. For such cases the safety margins of the PTV were redefined to at least 5–7 mm below the skin surface. Irradiation was done by an afterloading device (microSelectron PDR or HDR; Nucletron Corp., Veneendaal, The Netherlands) with an 192Ir source, at a source strength (air-kerma rate, Ka.100) for PDR-brachytherapy within a range of 1.2 mGy.m2/H ⬍ Ka.100 ⬍ 4.8 mGy.m2/H and for the HDR-brachytherapy within a range of 15 mGy.m2/H ⬍ Ka.100 ⬍ 45 mGy.m2/H. The dose calculation was performed by the Plato Brachytherapy Planning System (Nucletron Corp., Veenendaal, The Netherlands), using geometrical optimization. For PDR-brachytherapy, a dose per pulse with a median value of 0.60 Gy (range, 0.4–1.0 Gy) up to a median total dose of 49.8 Gy (range, 49.0–51.3 Gy) was prescribed. The pulses were delivered for 24 h/d, with an interval of 1 hour between pulses. For HDR-brachytherapy, a dose of 4 Gy per fraction up to a total dose of 32 Gy was prescribed. For dose specification and prescription, rules similar to the Paris system were used. Thus, the dose per pulse of 0.6 Gy, or dose per fraction of 4.0 Gy, corresponded to the reference dose (Dref) in this study, which was prescribed at 85% of the mean central dose. The volume of the 85% isodose was about 60 cm3, with a 150% isodose volume of
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∼7–9 cm ; the dose homogeneity index (DHI) values were ∼0.8 (Table 2). According Wu et al. (2), DHI was defined as a fraction of the volume of the reference isodose receiving dose between 100% and 150% of the Dref; DHI ⫽ [V(Dref) ⫺ V(D150)] · V(Dref)⫺1. 3
Systemic therapy Adjuvant sequential chemotherapy and/or hormone therapy was allowed according to the local protocol of the treating center (Table 1). The time interval from the definitive breast surgery to the start of brachytherapy was about 60 days. If patients received chemotherapy, the brachytherapy was done either before the systemic treatment, or was given in the interval between the chemotherapy courses—in most cases between the first and second course of chemotherapy. Altogether, 20/176 women (11.4%) received systemic chemotherapy. Sixteen patients (9.1%) received three or six cycles of epirubicin and cyclophosphamide (EC) with or without hormone therapy, 1 patient had six cycles of 5fluorouracil, epirubicin and cyclophosphamide (FEC) and 3 other patients (1.7%) had six cycles of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (for more details see Table 1).
Table 2 Brachytherapy parameters in all patients Parameters Interval of definitive surgery and brachytherapy (days) Average Range Number of implant tubes Average Range Implant volume (85% isodose) (cm3) Average Range Volume of 150% isodose (cm3) Average Range Dose homogeneity index Average Range Total dose (Gy) Average Range Dose per pulse (Gy/h/24h) Average Range Dose per fraction (Gy) Average Range
HDR brachytherapy (25% of all patients)
PDR brachytherapy (75% of all patients)
64 14–99
60 4–99
12 8–15
13 6–18
63.6 32.2–133.9
59.3 23.7–149.0
8.8 3.9–13.5
6.4 3.2–22.0
0.79 0.61–0.85
0.80 0.53–0.87
32 32–32
49.8 49.0–51.3
– –
0.60 0.40–1.00
4 4–4
– –
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Strnad et al. / Brachytherapy 3 (2004) 115–119
Statistical methods All patients were followed closely to analyze acute and late toxicity according to RTOG/EORTC and LENT-SOMA criteria, local control, and survival rates. All patients were included in the follow-up. The analysis was performed after a median follow-up of 12 months for the whole group of 176 patients and for a subgroup of 88 patients after a median follow-up of 21 months (12–39 months). Follow-up was calculated from the day of definitive surgery to the date of last follow-up. The primary endpoint of this analysis was the evaluation of treatment side effects. The secondary endpoint was the evaluation of the effect of brachytherapy on local control (local recurrence-free survival rate).
Results Treatment outcome At the time of analysis none of the patients, neither from the whole study group (176 patients, median follow-up 12 months) nor from the subpopulation (88 patients, median follow-up 21 months), developed ipsilateral or contralateral recurrence; likewise no patient showed clinical signs of distant metastases. Cosmetic results and side effects Only minimal acute side effects in a few patients, and mild late side effects, such as hypersensation, hyperpigmentation, fibrosis, or teleangiectasia, in 1–12% of all patients, were registered. Acute complications such as breast infection were recorded only in 1 patient (0.6%). The most frequent late effects were telangiectasia, grade I in 4.7% (8/172), grade II in 0.6% (1/172), and grade III also in 0.6% (1/ 172) of evaluable patients. Similarly, we observed fibrosis grade I in 7.6% (13/172) and grade II in 7.0% (12/172) of evaluable patients. Excellent or good cosmetic results have been observed in 92–95% of patients. Up to now it is not possible to find any differences in side effects according to the use of systemic therapy or to use of PDR- or HDRbrachytherapy. All acute and late side effects according to the RTOG/EORTC scoring, including cosmetic results are listed in Table 3.
Discussion The main advantage of brachytherapy as monotherapy in the organ conserving treatment of breast cancer is the potential to improve the quality of life for patients. We now have enough mature clinical data (3–9) demonstrating comparable long-term data—the same local control rates, survival rates, and minimal side effects compared with conventional whole breast radiotherapy (Table 4). Of course, proper patient selection and quality assurance are critical here. Inappropriate patient selection or suboptimal quality
Table 3 Side effects and cosmetic results from brachytherapy alone
Bleeding Hematoma Bacterial Implant infection Radiodermatitis Grade 1 Grade 2 Grade 3 Grade 4 Telangiectasia Grade 1 (⬍1 cm3) Grade 2 (1–4 cm3) Grade 3 (⬎4 cm3) Fibrosis Grade 1 Grade 2 Grade 3 Hypersensation Mild pigmentation Cosmesis (doctor’s opinion) Excellent Good Fair Poor Cosmesis (patient’s opinion) Excellent Good Fair Poor
All patients (n ⫽ 176)
Subgroup (n ⫽ 88)
0
0 0
1/176 (0.6%) 1/176 (0.6%)
1/88 (1.1%)
3/176 (1.7%) 2/176 (1.2 %) 0 0
4/88 (4.4%) 1/88 (1.1%) 0 0
8/172* (4.7 %) 1/172* (0.6%) 1/172* (0.6%) 13/172* 12/172* 0 2/172* 22/172*
(7.6%) (7.0%)
8/88 (9.1%) 1/88 (1.1%) 1/88 (1.1%) (11.4%) (4.5%)
(1.1%) (12.8%)
10/88 4/88 0 2/88 12/88
85/144* 50/144* 8/144* 1/144*
(59.0%) (34.7%) (5.6%) (0.7%)
47/88 34/88 6/88 1/88
(56.0%) (38.6%) (7.1%) (1.2%)
84/144* 48/144* 9/144* 3/144*
(58.3%) (33.3%) (6.3%) (2.1%)
45/88 28/88 8/88 3/88
(53.6%) (31.8%) (9.5%) (3.6%)
(2.3%) (13.6%)
* Some follow-up data were not available at the time of analysis.
assurance in the brachytherapy technique and/or target definition leads to unsatisfactory results. This is documented in some other trials (Table 5). The earlier data from this German-Austrian Trial were similar to the results presented in Table 4. We also believe that the long-term data and further analyses of our study will support the suggestion that brachytherapy alone is a reasonable approach for appropriately selected patients. The next step in this endeavor are the phase III trials, which begin this year in the US and Europe. Table 4 Results of selected large studies with proper patient selection and appropriate quality assurance Follow-up Recurrence Patients (n) (months) rate (%)
Institute (ref)
Technique
William Beaumont Hospital (8) Ochsner Clinic (5) National Institute of Oncology, Budapest (6–7) Virginia Commonwealth University (4) Present study
LDR/HDR
199
65
1.2
LDR/HDR HDR
160 45
84 70
2.5 4.4
LDR/HDR
59
50
5.1
PDR/HDR
176 69*
13 24
0 0
* Subpopulation of patients with 2-year follow-up.
Strnad et al. / Brachytherapy 3 (2004) 115–119 Table 5 Results of studies with inappropriate patient selection and/or suboptimal quality assurance in the brachytherapy technique and/or target definition Institute (ref.)
Follow-up Recurrence Technique Patients (n) (months) rate (%)
Christie Hospital (10, 11) EBI Guy’s Hospital (12) LDR London Regional HDR Cancer Center (13)
353 27 39
96 72 86
19.5 37 16.2
EBI ⫽ external beam irradiation.
Another question in this context is the appropriate brachytherapy technique. For partial breast irradiation, either the multi-catheter technique or the balloon system can be used. Each system has advantages and disadvantages. With the balloon system the advantages are: a short learning curve; treatment planning is simple and reliable in any center with a HDR remote-afterloader; good reproducibility; and only one puncture site. The main disadvantage of the balloon system is that despite some progress (14, 15) the target volume coverage compared with the multicatheter system is very limited in form and volume. With the multicatheter system, the main advantages are that the tumor parameters (inclusion criteria) are exactly known at the time of implantation and that the target volume coverage is not limited in form and volume. Further advantages of the multicatheter system are that it has very good reproducibility and the treatment planning is simple and reliable. Considered as possible disadvantages are more puncture sites (⬎10) and an individually-long learning curve. It is still not possible to say whether the balloon or the multicatheter system is better. The multicatheter system is very flexible and makes it possible to cover any form of target, but the balloon system is easy to handle. One has to await the results of the phase III studies to answer the above question. Conclusion Accelerated partial breast irradiation is a valuable therapy for appropriately selected low-risk breast cancer patients, but until results of phase III studies are published these patients should be treated in registered studies.
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