PTC CLINIC
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Proton RT Clinical Trials for Breast Cancer

Proton therapy approaches for breast cancer can be divided into two groups, according to the size of the irradiated volume. The first approach is Accelerated Partial Breast Irradiation (APBI), which is indicated for selected low-risk breast cancers. It represents a small irradiated volume, as is usually the tumor bed after a lumpectomy, with a 1-2 cm hem. The reduction of the irradiated volume makes it possible to deliver a higher dose to the target volume in a shorter irradiation period. A prospective phase II clinical study under the auspices of PTCOG PCG BRE007-12 prescribes a dose of 40 Gy in 10 fractions in several US centers. We do not yet perform APBI technology at the Proton Therapy Center in Prague. The second approach is Whole Breast Irradiation (WBI), chest wall with or without lymph node irradiation. We implement this regime at our center. The two regimens are compared in several clinical studies.

Randomized clinical trials comparing proton and photon radiotherapy are not yet available. Current work focuses mainly on acute toxicity and early outcomes. The results confirm the feasibility and acceptable toxicity of proton radiotherapy for the treatment of breast cancer.

Verma et al. published early results in proton radiotherapy for locally advanced breast cancer requiring irradiation of the internal mammary nodes. The authors describe the proton therapy techniques used and the treatment outcomes of a group of 91 patients. They evaluated the toxicity of adjuvant radiotherapy, the median follow-up was 15.5 months. RT interruptions due to toxicity are reported in 8% of patients. G3 dermatitis is reported in 5% of patients, which resolved within 32 days after radiotherapy.

Cuaron et al. evaluated early toxicity in 30 patients with locally advanced breast cancer. They evaluated the results of postoperative radiotherapy as well tolerated, with acceptable skin toxicity. McDonald et al. evaluated proton radiotherapy in 12 patients with locally advanced breast cancer after mastectomy. The authors describe that proton radiotherapy is suitable and well tolerated especially in selected patients with inappropriate cardiac anatomy and immediately after breast reconstruction.

Kammerer et al. published their meta-analysis, which included 13 studies evaluating older scattering technologies and the pencil scanning technique. The result showed better coverage of the target volume, but mainly a reduction in the mean cardiac dose of 1 Gy for proton radiotherapy versus 3 Gy for 3D conformal radiotherapy versus 6 Gy for IMRT.

Luo et al. published the results of proton radiotherapy in patients after mastectomy. The authors evaluated a cohort of 42 patients, with a median follow-up of 35 months. The result showed excellent locoregional control and favorable toxicity.

Cosmetic results of proton radiotherapy are available from two publications. Bush et al. published 5-year data in 100 patients treated with proton APBI. Patients were treated in the prone position, using the passive scattering technique and multiple fields (2-4). Treatment plans were prepared so that 90% isodose would not exceed the skin surface. At the 5-year of follow-up, the authors describe the cosmetic result as excellent and unchanged from the baseline. They consider this result to be better compared to photon techniques, mainly due to the reduction of the radiation dose to the whole breast and the use of skin-saving techniques.

Galland-Girodet et al. from MGH, Boston, published 7-year results in 98 patients treated with proton APBI and compared the cosmetic result with those of patients treated during the same period with photon APBI. At the same local control, patients treated with protons had worse toxicity in terms of telangiectasia, pigmentation and late skin reactions. Passive scattering (1-3 fields) was used for treatment. However, to increase the capacity of the irradiator, even when using more fields, only one field was irradiated every day, which the authors consider to be one of the possible causes of higher skin toxicity.

Chang et al. published the results of the passive scattering APBI technique in 30 patients with a median follow-up of 5 years who were treated with a 30 GyE regimen in 6 fractions. The authors reported excellent disease control, acceptable cosmetic effect, and suggest the use of multipole techniques.

Proton Therapy Dosimetric Studies in Breast Cancer

Proton radiotherapy offers better target volume coverage, even compared to state-of-the-art photon techniques such as Volumetric Modulated Arc Therapy (VMAT). Usual irradiation homogeneity of 95% volume receives 98% of the prescribed dose and only small regions receive 105% of the prescribed dose.

A great advantage of proton therapy in the treatment of breast cancer is the ability to minimize the dose to the lungs, the contralateral breast and especially to the heart in left-sided breast cancer. This reduces the risk of secondary malignancies of the contralateral breast and lungs. The benefits of VMAT was seen in both passive scattered proton therapy (PSPT) and intensity modulated proton therapy (IMPT). When using the controlled breathing method, proton radiotherapy achieves significantly better parameters than photon radiotherapy even with the passive scattering technique.

Taylor et al. compared mean cardiac doses for 3D compliant breath control and proton therapy based on an analysis of 149 published studies. They found that the average dose for 3D CRT was 4.2 Gy, for controlled breathing was 1.2 Gy and for proton radiotherapy was 0.5 Gy.

Stick et al. performed a comparative dosimetric study in 41 patients with left-sided breast cancer after lumpectomy who underwent photon radiotherapy. Irradiated volume included breast and lymph nodes. These radiation plans were compared with proton plans. The proton plans consisted of two direct SFO fields. The risk of cardiovascular toxicity was calculated and the risk of recurrence in the lymph nodes was determined, as the internal mammary nodes were purposefully irradiated in the case of photon plans. The authors concluded that modern photon therapy yields a limited risk of cardiac toxicity in most patients, but proton therapy can reduce the predicted risk of cardiac toxicity by up to 2.9% and the risk of breast cancer recurrence by 0.9% in individual patients. The dosimetric advantage of PBS is more evident when axillary and supraclavicular nodes are included in the target volume. IMPT brings an even greater benefit if internal mammary nodes are also included in the target volume.

Tommasino et al. came to similar conclusions. They performed a randomized dosimetric study in patients with left-sided breast cancer irradiated with conventional photon radiotherapy. The plans were created so that the coverage of the target volumes met the criteria given by the RTOG 1005 recommendation. There were always two variants of the plan: one optimized for skin preservation and the other not. The risks of damage to the skin, lungs, heart and individual cardiac sections were determined using the NTCP model. The use of IMPT has shown to provide significant radiation sparing to the heart and lung with the same tumor coverage. According to the NTCP model, lower acute dermal toxicity can also be expected for IMPT if the skin is included in the optimization. The resulting risk of complications for the heart is almost zero in the case of proton therapy with PBS. However, these planning studies do not take into account the effect of static change in the position of the irradiated volume (due to breathing) on the resulting dose distribution of the proton plan. In addition, the studies do not even describe the effect of self-breathing on the breakdown of dose distribution due to interplay effects.

The effect of the change in position was evaluated by Flejmer et al. They evaluated the effect of maximum and minimum breath and free-breathing on the dose distribution of both photon plans and IMPT plans in a group of 12 patients with left-sided breast cancer. The original plans were counted in the maximum breath and recalculated into the CT examination in exhalation. Plans calculated on CT in free-breathing were converted to CT examination in maximum breath. One single-pole plan and one three-pole plan were created for each case. Target volume coverage and critical organ dose were evaluated. The range in the sternal position between maximal inspiration and expiration was in the range of 0.5-14.6 mm. It turned out that the positional error caused by the breath or exhalation does not significantly worsen PTV coverage. The minimum dose of V98 decreased from 48-49 Gy to 46-47Gy and V95% decreased from 99-100% to 96%-98%. There was also a slight deterioration in the homogeneity of PTV irradiation, namely 4-6% to 8-11%. The dose to the lungs either increased or decreased the mean dose, depending on the direction of the recalculation. Overall, the effect of the change in position caused by respiration has been shown to be insignificant.

A similar study was performed by Öden et al. on 12 CT scans. Photon and proton plans were calculated in free-breathing. RBE 1.1 was calculated for the proton plans and they were robustly optimized. All plans were evaluated for robustness to positional errors caused by maximal inspiration and free-breathing. Along with robustness, the effect of RBE variability in the irradiated volume (RBE 1.14-1.24) and in the surrounding organs, where higher RBE values were calculated, was also evaluated. The effect of variable RBE was only marginal due to the small dose in critical organs, but should be taken into account. Both proton and photon plans have proven to be robust enough for the maximum shifts caused by breathing.