Simultaneous integrated boost for adjuvant treatment of breast cancer- intensity modulated vs. conventional radiotherapy: The IMRT-MC2 trial

Breast cancer is the most common cancer entity in women in developed countries, representing a major health care problem. The disease is diagnosed in about 1.2 million patients and accounts for about 500,000 deaths yearly worldwide [1]. Treatment is based on stage, histology and biomarkers and is commonly multimodal. The development of diagnostic strategies has led through the years to an earlier diagnosis of breast cancer, which resulted in the evolution from entirely surgical treatment into more conservative approaches, replacing mastectomy by breast-conserving surgery followed by radiation therapy in early-stage disease [2]. Adjuvant whole-breast external beam radiotherapy has been shown to result in a significant increase of local control, as well as a significant reduction in the risk of death [3], making the outcome of breast-conserving surgery comparable to mastectomy. Furthermore, additional boost-irradiation to the tumor bed is found to further improve local tumor control. In particular, 10-year cumulative incidence of local relapse in the randomized prospective trial comparing whole-breast irradiation versus whole-breast irradiation and subsequent boost was 10.2% versus 6.2% [4]. Further analyses have revealed an increased benefit for patients younger than 50 years and patients with high grade invasive ductal carcinoma [5].

The most common adjuvant radiotherapy strategy after breast-conserving surgery consists of irradiation of the whole breast using two tangential photon beams during a 5-6 week period, with doses of 1.8-2.0 Gy per fraction to a total dose of approximately 50 Gy. Thereafter, boost irradiation is carried out using electrons and/or photons up to a total dose of 66 Gy, resulting in total treatment duration of 7-8 weeks.

Dose escalation by a sequential boost regimen results in a longer treatment duration. Furthermore, various studies have demonstrated that higher radiation dose is associated with a limited but statistically significant worsening of the cosmetic result, mainly due to breast fibrosis. In particular, the risk of moderate or severe fibrosis at 10 years after breast conserving surgery followed by whole breast irradiation with or without boost-irradiation of 16 Gy was significantly increased for the group of patients that had received a boost (12.6% versus 26.9%) [6].

Another important aspect in radiation therapy of breast cancer is the fact that although radiotherapy is associated with reduced disease-specific mortality, an increase of cardiovascular mortality after radiation treatment has been shown, with a trend towards higher risk for women with left-sided disease [7]. Radiation associated cardiac disease can manifest either as acute injury, i.e. pericarditis, or as late injury, such as congestive heart failure, ischemia, coronary artery disease or myocardial infarction months to years post radiation therapy [8]. Volume-dependent perfusion defects after irradiation of left-sided breast cancer using tangential photon beams to a dose of 50 Gy and electron boost of 16-18 Gy has been revealed for up to 40% of patients within 2 years after treatment [9]. The risk for heart disease post-irradiation is higher for younger patients and is further enhanced by the established use of anthracyclines in multimodal treatment regimes [10].

The limitations in radiation therapy of breast cancer reveal the necessity for the use of advanced radiation therapy strategies that allow a more accurate delivery of radiation dose to the target volume sparing the surrounding healthy tissues. A promising technology to achieve this goal is intensity modulated radiotherapy (IMRT). IMRT is an advanced technique using computer-assisted inverse planning and administering radiation via multiple individual segments. Varying intensities across each beam allow improvement of dose homogeneity. Delivery of irradiation to irregularly shaped targets is optimized with IMRT, while the technology offers the ability to produce concavities in the treatment volume and therefore increase conformality. Trials in breast cancer patients have demonstrated better dose uniformity throughout the breast for intensity modulated radiotherapy with a median of 0.1% of the treatment volume receiving ≥110% of the prescribed dose versus 10% with conventional wedges [11]. Helical tomotherapy is an advanced technology for intensity modulated radiotherapy using an image-guided, dynamic, therapy delivery system, which offers the potential for pretreatment megavoltage CT imaging. Pretreatment imaging for patient positioning verification is of high importance, since it allows corrections for inter-fraction positioning errors, which is a prerequisite for accurate delivery of complex IMRT treatment plans [12]. Studies in breast cancer patients comparing tomotherapy with 3D-planning demonstrated a minimal dose increase but improved dose homogeneity and conformity to the planning target volume [13].

A major advantage of IMRT is also the fact that, in contrast to conventional techniques, it provides the possibility to integrate the boost concept in the daily radiation sessions by increasing the dose per fraction within the boost volume [14]. Hence, overall treatment duration can be shortened by more than one week compared to conventional radiation treatment in patients, who are likely to benefit from an additional boost to the tumor bed.

Thus, aim of this prospective, two-armed, multicenter, randomized trial is to compare the results of intensity-modulated radiotherapy versus conventional radiotherapy for adjuvant treatment of breast cancer. Rationale of the project is the reduction of treatment duration in view of at least consistent radiation toxicity, local control, disease-free survival and overall survival, with emphasis given to the cosmetic results and local control after adjuvant treatment.

The role of intensity modulated radiation therapy (IMRT) in the treatment of breast cancer has been subject of investigation in various trials within recent years. Most of the studies have performed dosimetric analyses of IMRT compared to other radiation therapy techniques. One of the first trials to directly compare IMRT tangential photon fields versus tangential photon fields with oblique electron-photon fields with manually optimized beam wedges and wide split tangential photon fields with computer optimized wedge angles in the treatment of breast cancer was performed by Cho et al. [20]. In this study, the root mean square deviation of the differential dose-volume histogram (RMS dDVH), which is a measure of dose homogeneity was found to be lower for IMRT compared to the other techniques, revealing an improved dose coverage to the treatment volume. In the same study, the normal tissue complication probabilities (NTCPs) for the organs at risk, i.e. heart and lungs, were calculated for comparison. The average NTCP for excess late cardiac mortality and radiation pneumonitis was calculated to be lower for IMRT, while the intensity-modulated technique also showed the lowest partial body mean dose. A further study from the same group has shown a 50% reduction of NTCP for late cardiac toxicity using tangential IMRT, compared to conformal tangential fields [21].

The dosimetric advantages of inversely planned IMRT in the treatment of breast cancer have been demonstrated by Thilmann et al. in a plan comparison study including 20 patients [22]. In all cases the homogeneity in the target volume was improved for the inversely planned IMRT compared to the 3D-planned conventional radiotherapy (CRT). The volume of the ipsilateral lung irradiated with a dose higher than 20 Gy was strongly reduced with IMRT compared to CRT (13.1% versus 24.6% respectively). A similar trend was noticed for the heart volume receiving a dose higher than 30 Gy (0.2% for IMRT versus 6.2% for CRT).

More recent studies have also confirmed superior dose distribution and homogeneity for IMRT, while also revealing that the use of intensity modulation leads to a reduction of the dose to the contralateral breast compared to conventional tangential field techniques. Bhatnagar et al. showed a reduction of 36% and 57% at 4 and 8 cm respectively from the center of the medial border of the tangential field on the contralateral breast when IMRT was used compared to 3D-technique, a result which was found to be highly significant [23].

Improvement of dose homogeneity with IMRT in breast cancer has a positive influence on clinical benefits for the patients in terms of reduced acute or late toxicity. Toxicity analysis of 172 breast cancer patients treated with either IMRT or with wedge-based radiotherapy showed a significant reduction in acute dermatitis grade 2 or worse, edema or hyperpigmentation when IMRT was applied. Chronic edema grade 2 or worse was also significantly reduced in favor of IMRT [24]. A significant reduction in the occurrence of acute radiation dermatitis using IMRT has also been demonstrated in a multicenter double-blind, randomized clinical trial of about 330 breast cancer patients, who were treated with either IMRT or standard radiotherapy with wedge compensation to a total dose of 50 Gy in 25 fractions with an additional boost of 16 Gy when necessary [25]. This study demonstrated a significant decrease in the occurrence of moist desquamation during or up to 6 weeks post radiation treatment for the IMRT group. In particular, 31.2% of the patients treated with IMRT showed acute radiation dermatitis, while the value was 47.8% for the standard treatment arm. The same study showed no correlation of IMRT with pain or quality of life, still the presence of moist desquamation did significantly correlate with both pain and a reduced quality of life.

Reduced acute and late toxicity of breast IMRT results in improved cosmetic results. A randomized trial of standard 2D-radiotherapy versus IMRT in about 240 breast cancer patients investigated change in breast appearance scored from serial photographs before and after radiation treatment. This study showed that 58% of the patients treated with 2D-radiotherapy had changes in breast appearance, compared to 40% of the patients treated with IMRT, while significantly fewer patients in the IMRT group had developed palpable indurations of the breast [26].

Several publications have confirmed the feasibility and dosimetric superiority to conventional plans, as well as a decrease of acute and late toxicity compared to conventional radiation therapy in recent year. Despite the fact that breast IMRT is a field of high interest, long-term, clinical data are mostly based on retrospective analyses. One analysis performed by McDonald et al. showed no statistically significant differences in overall survival, disease specific survival, freedom from ipsilateral breast tumor recurrence, distant metastasis, late toxicity or second malignancies between 121 patients treated with IMRT and 124 patients treated with conventional radiotherapy to a median dose of 50 Gy, followed by a boost to a median total dose of 60 Gy [27]. Still, the study showed a slight trend in favor of IMRT with the 7-year freedom from ipsilateral breast tumor recurrence value found to be 95% for IMRT and 90% for conventional radiotherapy.

Therefore, the aim of our prospective, randomized, multicentric, phase III trial is a thorough evaluation of adjuvant IMRT for cosmesis, long-term clinical outcomes and quality of life for breast cancer patients in comparison to conventional 3D radiation therapy. Treatment dose for both arms is calculated to be equivalent in consideration of the linear-quadratic model. Based on the results of previous studies we investigate the hypothesis of a better cosmetic result for breast IMRT with at least consistent radiation toxicity, local control, disease-free survival and overall survival. Furthermore, through boost integration in the IMRT plan, we aim to shorten the therapy duration of about one to two weeks compared to conventional treatment strategies.