Cyberknife® versus other PBI systems

For the application of PBI, different techniques such as brachytherapy, intraoperative radiotherapy (IORT), three-dimensional radiotherapy (3DRT) or intensity-modulated radiotherapy (IMRT) have been studied with similar results. ^{Reference Livi, Buonamici and Simontacchi12} SBRT in CK has emerged as a possible alternative in PBI (Stereotactic-PBI, S-PBI). It has a clear advantage over other techniques of external radiotherapy due to its tracking system. This system minimises setup error and allows to reduce treatment margins, from 2 to 2·5 cm expansion to 1–1·5 cm of PTV, considering patient movement, this is a clear advantage compared to other systems such as 3DRT or IMRT. In addition, SBRT compared to brachytherapy is a non-invasive technique with less risk of infection.

Goggin et al. ^{Reference Goggin, Descovich, McGuinness, Shiao, Pouliot and Park13} performed a dosimetric comparison between CK and other external radiotherapy systems in PBI. Nine patients treated with lumpectomy were included. The treatment volume in CK was defined as the lumpectomy cavity with a total margin of 12 mm. In this study, a dose of 30 Gy in five fractions was prescribed. In 3DRT, the lumpectomy cavity was defined with a total margin of 25 mm. In this study, the prescription dose was 38·5 Gy in 10 fractions. Planning target volume (PTV) coverage and dose to critical structures were similar in both plans, except V5 was lower in 3DRT, 6·2% versus 39·4% in CK Iris collimator and 17·9% in multileaf collimator (MLC). CK showed a contralateral breast V50 of 25·5% in Iris collimator and 24·2% in MLC compared to 3DRT (56·2%). Plans with CK were more conformant than with 3DRT. Treatment times were approximately 50% shorter and the number of monitor units was 50% less, with MLC being more common than Iris collimator. Treatment time was similar to MLC and 3DRT. However, it should be considered that comparing two dosimetric methods with different margins and different prescriptions includes an important variable of confusion. Heinzerling et al. ^{Reference Heinzerling, Ding and Ramirez14} compared 3DRT and CK. The authors reported better coverage with CK, V15% in ipsilateral lung, maximum dose in heart, and V50% and V100% lower ipsilateral breast, but higher dose in skin. However, the same treatment volume was used ignoring the tracking advantages of CK. Fan et al. ^{Reference Fan, Hayes and Freedman15} compared CK, IMRT, miniphoton tangents and electrons as a boost. Of the four modalities, CK showed better dose distribution, low maximum dose in lung, low V20 and V40 in ipsilateral lung, low dose in skin and heart using MLC. Xu et al. ^{Reference Xu, Chen and Grimm16} compared their results with the available literature, CK was superior to IMRT or 3DRT except for the very low doses. Treatment with IMRT or 3DRT requires the inclusion of large volumes of breast, which has led to significant rates of fibrosis with poor cosmetic outcomes. ^{Reference Hepel, Tokita and MacAusland17,Reference Shah, Wilkinson and Lanni18}

The major disadvantage for PBI with IORT is that the definitive pathological anatomy is not always available. In addition, the dose is administered at 1 cm, but recurrences have been described at more than 1 cm. S-PBI is performed with the definitive pathological anatomy, being a less invasive treatment, the volume of the PTV is covered by the prescribed dose, and the plan is image based. The differences between IORT and interstitial brachytherapy are the inclusion of the cavity and 1 cm or 1·5 cm, respectively. ^{Reference Keisch, Vicini and Kuske19}

Technical requirements in PBI in CK

After clinical selection of patients, 4–5 weeks up to 12 weeks after lumpectomy, administration of PBI treatment in CK requires placement of fiducial markers in the proximity of the lumpectomy cavity.

Surgical clips assist in the delineation of the post-operative seroma cavity and fiducials, usually of gold, are used to allow the tracking. Fiducials can be implanted intraoperatively during surgery, but the definitive pathological results will not be available until a few weeks later, so the indication for PBI at that time will not be definitive. The placement of ultrasound-guided fiducials has been studied. ^{Reference Yang, Tao, Elkhuizen, van Vliet- Vroegindeweij, Li and Powell20}

A number of recommendations should be followed for their placement. First, the oncologist and radiologist delineate the cavity area on the skin and local anaesthesia is injected. The fiducial markers should be placed inside the parenchyma, at least 1–2 cm outside the cavity and with a separation between them of more than 18–20 mm, with a distance of less than 10 cm. It is important to place them in different planes, with a 15º angulation avoiding overlapping in the X-ray at 45º. The placement of a minimum of three fiducials is recommended. ^{Reference Seiler, Rahimi and Choudhery21} After the procedure, a mammography is performed to check the correct placement of the fiducials in different planes.

Rahimi et al. ^{Reference Rahimi, Thomas and Spangler22} used three–four ultrasound-guided gold fiducials around the lumpectomy cavity and two on the breast surface. In the study by Obayomi-Davies et al., ^{Reference Obayomi-Davies, Kole and Oppong23} they used four gold fiducials of 2 mm implanted in the seroma cavity guided by ultrasound, using at least three for tracking. Patients with poor breast integrity or large seromas were not considered as candidates. Vermeulen in 2011 ^{Reference Vermeulen, Cotrutz and Morris24} used four–five CT-guided 2 mm gold fiducials, if there were difficulties, it was defined by MRI. In 11 tumours, the fiducials were sutured into the cavity by the surgeon, one upper, one lower, medial, lateral and in-depth.

Immobilisation in PBI in CK

It is recommended that the planning CT should be performed at least 1 week after the placement of the fiducials. ^{Reference Obayomi-Davies, Kole and Oppong23} Simulation and planning were performed 3 days prior to treatment in the study by Vermeulen et al. Vermeulen et al. ^{Reference Vermeulen, Cotrutz and Morris24} in their study placed the patients in supine, head first and arms at the sides with an alpha cradle. The light-emitting diodes (LEDs) were placed on the ipsilateral breast. The CT included an extension from the mandible and several centimetres below the inframammary line. The CT slices were 1·25 mm. However, Meszaros et al. ^{Reference Mészáros, Smanykó and Major25} performed the CT slices every 5 mm. Rahimi ^{Reference Rahimi, Thomas and Spangler22} used a vacuum mattress, and a bra system for breast immobilisation, thus also holding the contralateral breast, preventing it from being placed on the other breast.

PBI contouring in CK

Treatment volumes included CTV and PTV, as there was no GTV. In the study by Seiler et al ^{Reference Seiler, Rahimi and Choudhery21} , CTV included the surgical bed with the surgical clips and the seroma, and 20 mm of expansion limited to the breast, the pectoral muscle and 5 mm of the skin surface. The PTV included the CTV and 2 mm of margin. However, Vermeulen et al. ^{Reference Vermeulen, Cotrutz and Morris24} used a CTV margin of 10–15 mm using MRI contouring with T2 or STIR sequences. Yoo et al. ^{Reference Yoo, O’Daniel, Blitzblau, Yin and Horton26} included a CTV margin of 10–15 mm and a PTV margin of 3–5 mm. Obayomi-Davies et al. ^{Reference Obayomi-Davies, Kole and Oppong23} included a CTV to PTV margin of 5 mm. Rahimi et al. ^{Reference Rahimi, Thomas and Spangler22} used a CTV margin of 15 mm, without a PTV margin. There is no clear consensus on this. ^{Reference Zhen, Zhao, Wang and Timmerman27}

Treatment dose in PBI at CK

The justification for hypofractionation in breast cancer is due to the low alpha/beta rate of the breast.

The single dose in PBI has been investigated with promising results, ^{Reference Iaccarino, Pinnaro and Landoni28–Reference Nichols, Dhople, Mohiuddin, Flannery, Yu and Regine34} allowing reduction of treatment. However, the most widely used schemes are hypofractionated.

Rahimi et al. ^{Reference Rahimi, Thomas and Spangler22} published a phase 1 study of dose escalation from 30 Gy to 40 Gy in five fractions. The prescription isodose was 95% and 99% of the PTV received a minimum of 90%. Meszaros et al. ^{Reference Mészáros, Smanykó and Major25} in a phase II study included 27 patients treated with 25 Gy/4 fractions daily. Vermeulen et al. ^{Reference Vermeulen, Cotrutz and Morris24} used doses of 30 Gy in 5 fractions in 2 patients, and 34 Gy in 10 fractions in 7 patients, with estimates based on breast cancer alpha/beta rate of 4·6 Gy and alpha/beta rate of 3·4 Gy for late toxicity. The mean prescription isodoses was 70% (range 65–76%) at PTV and the mean PTV volume was 114 cc (range 39–241 cc). Yoo et al. ^{Reference Yoo, O’Daniel, Blitzblau, Yin and Horton26} treated 8 patients with 15 Gy, 8 patients with 18 Gy and 34 patients with 21 Gy. Obayomi-Davies et al. ^{Reference Obayomi-Davies, Kole and Oppong23} included 10 patients treated with 30 Gy in 5 daily fractions, equivalent to 50 Gy in 25 fractions with an alpha/beta for 4 Gy tumour control. Prescription isodoses was 80% with Monte Carlo, 100% of the PTV received the prescription dose, the mean PTV was 70 cc. Ipsilateral lung V9 was 3%, and contralateral lung V1·5 Gy was 31%. The maximum skin dose was 36 Gy. The mean number of beams was 155 (119–194 beams). Lozza et al. ^{Reference Lozza, Fariselli and Sandri35} included 20 patients using CK with the Iris collimator with a prescription dose of 30 Gy in five fractions at 95% isodoses to PTV, with a median PTV of 88·1 cc and 60 minutes treatment duration (35–120 minutes).

Results and toxicity

Vermeulen et al. ^{Reference Vermeulen, Cotrutz and Morris24} described no recurrence after a median follow-up of 7 months (range 4–26 months). In the study by Obayomi-Davies et al., ^{Reference Obayomi-Davies, Kole and Oppong23} there were also no relapses at 3 years. In the study by Lozza et al. ^{Reference Lozza, Fariselli and Sandri35} after a median follow-up of 2 years, no relapse was observed. Acute toxicity occurs in the first 90 days after treatment and late toxicity after 90 days of treatment.

Rahimi et al. ^{Reference Rahimi, Thomas and Spangler22} described in their dose-escalation study 65 patients with acute toxicities and 47 patients with late toxicities. Most patients presented acute grade 1 toxicity, only two patients presented grade 2 acute toxicity consisting of axillary paresthesia and dermatitis. Most of the late toxicities were grade 1, five patients presented grade 2 late toxicities including breast pain, rib fracture and fibrosis. In the rib fracture patient, the V100 was 1·71 cc, with a maximum dose of 45·24 Gy, conformance index of 1·48. Only three patients experienced grade 3 toxicity at the 37·5 Gy dose level consisting of cellulite with grade 3 fibrosis and grade 3 dermatitis resolved without problems. Only one grade 3 dermatitis was dose limiting at 40 Gy in five fractions. Ten patients presented fat necrosis and four patients asymptomatic. Of the 10 patients with fat necrosis, the cut point was at a PTV ≥ to 124 cc. 95·9%, 100%, 96·7% and 100% at 6, 12 and 24 months were classified as excellent and good aesthetic results. Other constraints included skin < 39·5 Gy (exceeded in two patients), the protocol suggested the use of separate fractions at least 40 hours apart. In the study by Meszaros et al., ^{Reference Mészáros, Smanykó and Major25} there were no major grade 2 toxicities. Toxicities included grade 1 dermatitis in 22·2% of patients, grade 1 oedema in 11·1% and grade 1 pain in 3·4%. Cosmetic results were excellent in 62·9% and good in 37·1%. Vermeulen et al. ^{Reference Vermeulen, Cotrutz and Morris24} found minimal-to-moderate fatigue 2–3 weeks after the start of treatment, similar to fatigue after surgery. All toxicities were mild. The late cosmetic result was between excellent and good.

In the Obayomi-Davies study, ^{Reference Obayomi-Davies, Kole and Oppong23} all patients presented excellent cosmetic results. The side effects described in the study by Lozza et al. ^{Reference Lozza, Fariselli and Sandri35} were all mild, and more than 80% of the patients presented excellent cosmetic results.

Some recommendations for follow-up of these patients are included in the study by Vermeulen et al ^{Reference Vermeulen, Cotrutz and Morris24} , recommending follow-up at 4 weeks, 6 months and annually, including quality of life questionnaires and mammography at 6 months and annually thereafter.

Other indications for breast SBRT

In addition to PBI, the use of SBRT in breast cancer is expanding in other scenarios including inoperable patients as definitive treatment or as neoadjuvant treatment.

The radiobiological advantages of SBRT include the ablative effect on the tumour, enhancing different mechanisms of tumour destruction. This treatment increases the direct cytotoxic damage derived from the double breakage of the DNA and the stem cell, in addition to the microvascular and stromal damage in the tumour tissues. SBRT can enhance the anti-tumour immune response. Some studies, such as that of Shibamoto et al ^{Reference Shibamoto, Murai and Suzuki36} , have analysed the use of exclusive radiotherapy in conventional linear accelerators. In this study, 18 patients were included with 3 dose levels: 50 Gy/25 fractions; 18–25·5 Gy/3 fractions and 20 Gy/8 fractions. Overall survival, progression-free survival and local control were 93%, 85% and 92%, respectively, at 3 years. One patient died from lung metastases, another patient developed liver metastases at 90 months and a patient with local relapse with a tumour at diagnosis of 51 mm. Seven patients presented grade 1 dermatitis and 11 patients presented grade 2 dermatitis.

Neoadjuvant radiotherapy in breast cancer improves tumour oxygenation by irradiating small volumes and reducing the dose to healthy tissue. In addition, it allows to include the area of carcinoma in situ assisting the use of MRI.

Guidolim et al. ^{Reference Guidolin, Yaremko and Lynn37} included patients with early stage, less than 3 cm, oestrogen receptor positive, axilla clinically negative, with tumours at least 2cm from the skin, limited to 5 mm, and chest wall in a phase I preoperative single-dose study. All patients underwent prone MRI and CT scans. The prescription dose was 21 Gy to the primary tumour followed by surgery 1 week later. Twenty-seven patients with excellent cosmetic results and preserved quality of life were included. There were no major toxicities at grade 3. The cosmetic result was good or excellent in more than 92% of the patients. The authors conclude that this treatment is feasible and safe. Bondiau et al. ^{Reference Bondiau, Courdi, Bahadoran, Chamorey, Queille-Roussel, Lallement, Birtwisle-Peyrottes, Chapellier, Pacquelet-Cheli and Ferrero38} in their phase I study according to the chemotherapy scheme, SBRT with doses of 19·5 Gy/3 fractions and 22·5 Gy/3 fractions followed by WBI at 50 Gy. With CTV including GTV and 5 mm, and PTV including CTV and 2 mm. Surgery was performed at 4–8 weeks, with two complete responses and four patients with partial response, without increased toxicity.

CK has advantages in PBI over radiotherapy in LINAC, IORT or brachytherapy. In 3D radiotherapy or IMRT in LINAC, the treatment volumes are higher than CK. IORT is performed without having the definitive pathological anatomy with treatment volumes limited by the technique itself. Organisation with surgical teams is another complication. The correct placement in the tumour bed is operator and situation of the tumour bed dependent, without being able to correct coverage defects once placed. Finally, brachytherapy is an invasive technique. For the administration of PBI in CK, the placement of fiducial markers is necessary. A week later, a planning CT scan is performed with the patient placed on a mat and a breast support system is recommended. Treatment volumes include CTV and PTV. The extent of these volumes varies according to the authors. Doses vary from 25 to 34 Gy and between 4 and10 fractions. No long-term local control results are available. Side effects are very limited. SBRT in breast cancer is being studied in inoperable patients or as a neoadjuvant strategy.