European Mammo Site Brachytherapy Trials

APBI with interstitial BT using multicatheter systems requires high experience in all members of the staff. For that reason a new and simple BT system was developed in the US (Edmundson et al. 2002). The MammoSite radiation treatment system (RTS) is a dual lumen spherical balloon catheter. One lumen allows inflation of the balloon to diameter of 4-5 cm; the other provides a pathway for the 192Ir source. The advantage of this system is that only one applicator is implanted to perform fractionated radiotherapy of the tumor bed as compared to interstitial BT, which requires up to 20 needles. Since 2002 this system has been available for commercial use. In the US, the system is used by many institutions in the their daily practice. In Europe several feasibility studies have been initiated to investigate the practicability and safety of the system (Niehoff et al. 2005). Most of these trials were designed to test the device as the sole method for APBI and for delivery of a boost dose in combination with whole-breast EBI.

Up to June 2005 the MammoSite applicator had been implanted in 87 patients in different institutions in Europe (Table 16.5). Eligibility criteria for the sole modality (boost modality in parenthesis) were: age >60 years (boost: age >40 years); tumor <2 cm (boost: <2.5 cm); invasive ductal histology; grade 1/2 (boost: grade 2-3); margins >5 mm (boost: negative margins); applicator placement within 10 weeks of final lumpectomy procedure; and excision cavity with one dimension of at least 3.0 cm. In contrast to the American studies (Harper et al. 2005; Shah et al. 2004; Vicini et al. 2004b) a skin-balloon distance of at least 7 mm was demanded. Exclusion criteria were: presence of EIC, pure intraductal cancer (pTis), lobular histology, multifocal or multicentric lesions, or collagen vascular disease. The implantation, treatment planning and treatment performance was similar to the American trials described in Chapter 10. The applicators were preferably implanted during the final lumpectomy. In one institution a drain was inserted into the cavity to prevent air bubbles and hematoma, and to maintain optimal tissue conformance to the balloon surface. For sole MammoSite therapy a total dose of 34 Gy in ten fractions (prescribed at 1 cm from the balloon surface) was delivered over 5-7 days. In the boost group a total dose of 10-20 Gy was delivered with a fraction dose of 2.5 Gy over 2-4 days. In both groups, two daily fractions were delivered with a minimum of 6 hours between fractions. Patients were treated with various commercially available HDR remote afterloading machines.

Table 16.5 Implanted patients in European MammoSite studies listed by country

Country

Primary

Boost

Not treated

Total

France

22

-

11

33

Germany

10

2

7

19

Italy

13

-

2

15

Hungary

1

11

1

13

Switzerland

2

3

-

5

Austria

2

-

-

2

All countries

50

16

21

87

Overall 87 patients were enrolled in the European studies. Out of 87 implanted patients 21 (24.1%), had to be excluded from the clinical trial. The most common reason for exclusion was the final pathology. At the final decision, 50 patients were eligible for BT alone and 16 patients were treated with a boost BT followed by whole-breast EBI. No LRs have been reported after a mean follow-up of 12 months (range 1-31 months). One patient died of intercurrent disease 2 years after treatment, and another disease-free patient suffers from stomach carcinoma. In all patients the anatomic position of the device to the skin and to the chest wall was verified before and during the treatment. With the daily fluoroscopic simulations a balloon rupture was detected in two patients, one prior to and one in the course of treatment. One patient was excluded; the other patient finished the treatment after reimplantation of a new balloon. The devices were returned to the manufacturer for analysis and in each case the balloon damage was consistent with contact with a suturing needle or suture material. Because of this, we recommend cavity closure with a deflated balloon.

CT-based treatment planning is required to define the balloon-skin distance and to detect air pockets and hematoma. An insufficient skin distance of less than 7 mm leads to an overdosage at the small skin vessels. A subgroup analysis of the 32 German and Hungarian patients showed that the mean balloon-to-skin distance was 12 mm (range 3-36 mm), and it has a strong correlation with the breast cup-size. Calculated skin dose was between 65% and 132% of the reference dose. The DHI of 0.71 (range 0.61-0.83) was the same as the DHI (0.71) using multicatheter BT (Polgar et al. 2000).

Air pockets and hematoma of more than 3 mm lead to an underdosage of relevant breast tissue. The air gap volumes of 31 patients were analyzed in the German-Hungarian study. The measured mean air gap volume with or without a drain was 0.01% (range 0-2%) and 0.97% (range 0-4.8%) of the PTV, respectively (P=0.01).

The side effects in patients (n=24) treated in Germany and Hungary are listed in Table 16.6. The most common toxicity was mild or moderate erythema in the high skin dose area with or without desquamation. Other less-common events were: hyperpig-mentation, mastitis, seroma, abscess, edema and fistula. Five serious adverse events were recorded, three of which were device related (two abscesses and one fistula). Patients who developed an abscess show only minor cosmetic deterioration at a follow-up of 1 year. No abscess was observed in patients receiving antibiotic prophylaxis.

For the Hungarian and German patients the D90 (minimum dose to 90% of the target volume) was 98% (range 84-112%), which is higher than that reported in the literature

Erythema Hyperpigmentation Seroma Abscess

Erythema Hyperpigmentation Seroma Abscess

Mastitis

Desquamation

Fistula

Fibrosis

Edema

Fat necrosis

Telangiectasia

Serosanguine-ous leakage

Table 16.6 Side effects in 24 patients irradiated (subgroup analysis of the German-Hungarian MammoSite study)

(Edmundson et al. 2002). High dose volumes never exceeded the literature reported volumes for fat necrosis (Shah et al. 2004; Wazer et al. 2001).

Antibiotic prophylaxis and stringent wound care recommendations seem to be indispensable. The abscess rate (8%) in the German-Hungarian study was lower than that reported by others (Harper et al. 2005; Shah et al. 2004; Vicini et al. 2004b). No abscess was seen after introduction of antibiotic prophylaxis. Harper et al. (2005) reported a 16% abscess rate. An infection rate of 9.2% including breast infection, mastitis, cellulites and abscess was observed in the American Society of Breast Surgeons Registry study (Shah et al. 2004; Vicini et al. 2004b).

The balloon surface to skin distance is a critical point in terms of avoiding toxicity. In Europe a minimum skin distance of 7 mm was allowed. Van Limbergen et al. (1989) reported that the risk of telangiectasia is increased if doses for the subcutaneous skin vessels exceed 46 Gy. Van Limbergen et al. (1987, 1990) also emphasized that any overlapping of the high dose areas of the interstitial implants with the upper 5 mm of the subcutaneous tissue should be avoided. Turreson (1990) reported that there is an interval of 5 years before telangiectasia appears. We observed telangiectasia in 8% of our patients 1 year after irradiation with the MammoSite RTS. It has to be underlined that we need a longer follow-up to know the final risk of telangiectasia after using balloon BT.

Based on the early European experience, the MammoSite device is simple and safe to handle. The acceptance of the system by the patients is very high and we believe that the device will offer an alternative method for postoperative partial breast brachytherapy for a highly selected group of patients. Additional studies and long-term follow-up of existing studies are recommended in order to further define and potentially expand the patient selection criteria as well as to assess long-term local tumor control and late tox-icities. Reimbursement in Europe is as yet unclear. In most European countries the immense costs of the applicator are not taken over from the health insurance companies, but an all-inclusive amount is paid for the treatment. Until the issue of reimbursement is clarified the MammoSite RTS will remain financially unattractive in Europe.

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