| | Phase I–II studies on accelerated IMRT in breast carcinoma: Technical comparison and acute toxicity in 332 patients☆Received 29 April 2008; received in revised form 23 October 2008; accepted 23 October 2008. published online 17 November 2008. Abstract Background and purposeTo evaluate the results in terms of dosimetric parameters and acute toxicity of two clinical studies (MARA-1 and MARA-2) on accelerated IMRT-based postoperative radiotherapy. These results are compared with historical control group (CG) of patients treated with “standard” 3D postoperative radiotherapy. ResultsThree hundred and thirty two patients were included in the analysis. Dosimetric analysis showed Dmax and V107% reduction (p <0.001) and Dmin improvement (p<0.001) in the PTV in patients treated with IMRT. Grade 2 acute skin toxicity was 33.6%, 13.1%, and 45.1% in the CG, MARA-1, and MARA-2, respectively (p<0.001), and grade 3 acute skin toxicity was 3.1%, 1.0%, and 2.0%, respectively. Similarly, larger PTV and use of chemotherapy with anthracyclines and taxanes were associated with a greater acute toxicity. With a median follow-up of 31 months, no patients showed local or nodal relapse. Postoperative radiotherapy is a part of conservative therapy of breast carcinoma. Conventional radiotherapy is based on the tangential technique with two photon beams frequently followed by a sequential boost with electron beam delivered to the tumor bed. According to the used doses (50Gy in 25 fractions of 2.0Gy +/− boost), radiotherapy lasts between 5 and 7weeks. To limit the engagement of the patient and of radiotherapy divisions, accelerated-hypofractionated regimens (dose per fraction higher than conventional one) have been proposed. They allow radiotherapy completion in 3–5weeks with cost reduction [1]. However, shorter overall treatment time results in greater injury in terms of early reactions. Therefore, accelerated regimens are theoretically associated with worsened acute toxicity. Moreover, late reactions show a high fractionation sensitivity. Consequently, the use of hypofractionated regimens may increase late toxicity, thus worsening the cosmetic result. Nevertheless, several clinical experiences with these regimens have shown acceptable late toxicity [2], [3], [4], [5], [6]. On the contrary, other authors have reported an increased late toxicity and poorer cosmetic results [7]. Therefore, hypofractionated regimens can be hindered by the increased risk of acute and especially late side-effects. In a recent years, for postoperative radiotherapy of breast carcinoma, intensity-modulated radiation therapy (IMRT) has been proposed. Several studies on treatment planning [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], in vivo dosimetry [25], [26] and preliminary clinical experiences have been published [27], [28]. Inverse planning was applied in some studies [8], [20], [24], [27], while a simplified approach, based on forward planning, was widely applied in many others [9], [11], [12], [15], [17], [19], [23], [28]. The results of dosimetric studies have shown IMRT to be able to improve the homogeneity of dose distribution [10], [11], [12], [17], [18], [19], [20], [23], [24], to reduce the dose to the heart [14], [15], [16], [20], [21], [24], the lungs [17], [20], [21], [24], and controlateral breast [20] and to improve dose distribution on the target [11]. In vivo dosimetry confirmed the reduced controlateral breast irradiation [26]; moreover it confirmed the reduced diffuse irradiation caused by the use of filters [25]. Preliminary clinical studies have shown a moderate skin toxicity in patients undergoing IMRT [23], [27], [28], [29] and a significant reduction of change in breast appearance as compared to conventional radiotherapy [30]. Therefore, IMRT is a potentially promising postoperative therapy for breast carcinoma due to the improved target dose homogeneity. In brief, accelerated-hypofractionated regimens can allow an overall reduced duration of treatment, which can be significant if associated with a total dose lower than the standard one. This approach could be used for patients at low risk of recurrence. On the contrary, if these regimens are used with standard doses, a better local control can be expected when considering the low α/β ratio (about 4) estimated for this neoplasm [31]. This approach could be advantageous for patients at higher risk of local recurrence [32]. Obviously, in this case, a higher acute and mainly late toxicity should be expected due to the higher equivalent dose to the normal tissues (α/β ratio: 2–3). In both situations, IMRT might lower the risk of side-effects, consequently favouring the use of accelerated-hypofractionated regimens. In fact, IMRT, due to improved homogeneity of dose distribution, reduces the degree and extent of hot spots and thus, the risk of complications. Based on these assumptions, the aim of this study was to evaluate the dosimetric and preliminary clinical results (acute toxicity) of forward-planned IMRT with accelerated-hypofractionated regimens. The results of two phase I–II studies were analyzed and compared with those of a group of patients who are previously treated with the 3D technique and standard doses. Comparisons were carried out in terms of the impact on dosimetric parameters as well as on acute toxicity. Materials and methods  Studies characteristics and inclusion criteria End-point Both the studies (MARA-1 and MARA-2) were single arm phase I–II trials. The same end-points were defined for both the studies. Primary end-point was the evaluation of late toxicity. Secondary end-points were the improvement of dosimetric parameters by the use of IMRT, acute toxicity, local control, and survival. Study design Both studies were planned to rule out a 10% increase in late (cutaneous and subcutaneous) grade ⩾2 toxicity at 3years from therapy. The incidence of about 5% of cutaneous and subcutaneous toxicity recorded in a preliminary analysis in the Control Group (CG) was considered. The sample size (for each of the two samples) to detect a significant difference (5% level of bilateral significance) for 80% potency was of 160 patients [34]. Considering the risk of patients who were lost to follow-up or were not assessable for late toxicity due to early death, it was established to enroll 200 patients for both the studies. Treatment planning In all patients, a CT-planning was used. At the time of CT scanning, the patient was placed in the treatment position (supine position with one arm raised). An alpha-cradle was used to ensure setup reproducibility. Contiguous 5-mm CT axial images were obtained extending from the larynx to the upper abdomen, including the entire breasts and lungs bilateral. Treatment was performed with the tangential technique and slight beam (not opposed) angulation to reduce the dose to the organs at risk (OARs). In patients also undergoing supraclavicular irradiation (only CG and MARA-2 study), the technique with a single isocenter was performed. Caudal to the isocenter the breast volume was irradiated with the tangential technique. Cranial to the isocenter the supraclavicular volume was irradiated with 2 opposed beams. Their angulations were optimized to prevent spinal cord irradiation. In all patients, dose reference was performed according to the ICRU report 62, even though the intrinsic difficulties in achieving a homogeneous dose in the breast tissue did not allow to comply with the minimum (95%) and maximum (107%) dose limit to the PTV in all patients. CTV1 and CTV2 were defined. The CTV1 was defined as tumor bed. Contouring was performed based on preoperative mammography, type of surgery, position of surgical clips and identification on CT-simulation scans of areas of surgical breast rearrangement. The CTV2 was defined as the whole breast excluding the most external cutaneous-subcutaneous 5mm (except for pT4 for cutaneous infiltration). PTV1 and PTV2 were obtained by adding 8-mm margin to the corresponding CTVs, directed in cranial, caudal, medial, and lateral directions. In CG patients, PTV2 irradiation was performed with two conformed tangential beams with standard MLC, of suitable energy (usually 6MV) with wedge filters. PTV1 irradiation was performed with direct electron beam of suitable energy. In patients undergoing IMRT, a forward technique was used for treatment planning optimization. In all patients for PTV2 irradiation, the dose to each of the two tangential beams was divided into two different segments (Fig. 1). One segment was designed to include the whole breast without filters (6MV photons). This configuration, in the absence of filters results in a volume of under dosage in the thickest region of the breast. A second segment was directed to this area of under dosage to compensate for dose loss (15MV photons). The weight of the two segments was determined by an iterative process repeated by the operator to the attainment of the optimal result. The PTV1 was treated with two conformed tangential photon beams with standard MLC and wedge filters at the same time of PTV2. Photon and electron beam dose calculation algorithm employed by Plato Sunrise treatment planning system (Nucletron B.VC., Veenendaal, The Netherlands) is a three-dimensional pencil beam, and has been described by Bortfeld [35]. It comprises a convolution-based approach, where the energy fluence distribution is convolved with a dose pencil beam. Inhomogeneity correction was applied by the equivalent tissue air ratio (ETAR) method. Treatment In CG patients, a tangential 3D technique was used. The PTV2 (residual breast) received 50.4Gy in 1.8Gy/fraction. The PTV1 (tumor bed) received a sequential electron boost of 10Gy in 2.5Gy/fraction. In MARA-1 study, patients were treated with IMRT. The PTV2 (residual breast) received 40Gy in 2.5Gy fractions. The PTV1 received a concomitant boost of 4Gy in 0.25Gy/fraction, delivered with 3D technique, photon beams and wedge filters. In MARA-2 study, patients were treated with IMRT. The PTV2 (residual breast) received 50Gy in 2.0Gy/fraction). The PTV1 (tumor bed) received a concomitant 3D boost of 10Gy in 0.4Gy/fraction delivered with 3D technique, photon beams and wedge filters. In all patients undergoing adjuvant chemotherapy, radiotherapy was started at least 3weeks after systemic treatment. In all patients daily portal images in the first phase of irradiation (5–10 MU) were acquired on both beams. Deviations larger than 5mm in the isocenter position were immediately corrected. Toxicity was scored prospectively in all patients groups, using the same timing and scoring system. All patients were evaluated at least once a week with clinical examination. Supportive therapy was similar in all groups of patients: Biafin was applied daily on the irradiated skin. In patients with grade 1–2 toxicity, steroids were administered topically. In patients with grade 3 toxicity, treatment was discontinued until grade 2 toxicity was resumed. Acute skin toxicity was differentiated based on the site (breast or supraclavicular region). Overall treatment time was of 32 fractions for CG (6.4weeks); 16 fractions for MARA-1 study (3.2weeks) and 25 fractions for MARA-2 study (5weeks). Dosimetry The impact of radiotherapy technique was evaluated on a series of parameters: Dmax, Dmin, V95%, and V107% of PTV, Dmean of the lung and Dmean of the heart. On the same parameters the impact of PTV in cm3 was evaluated. Follow-up Six months clinical examination was performed in all patients during follow-up. Every 12months, bilateral mammography was performed. For late cutaneous and subcutaneous toxicity, the sites of side-effects were separated (breast versus supraclavicular region). Statistical analysis Performance status was evaluated based on the ECOG scale [36]. TNM staging was performed according to the UICC classification [37]. Data were analyzed with R (version 2.6.1 Copyright (C) 2007 The R Foundation for Statistical Computing). The comparison between the two techniques in terms of dosimetric parameters was performed by analysis of Covariance with covariate the PTV. Results are reported in terms of mean values±standard deviation. The described analyses were conducted on the patient global population as well as by excluding the patients undergoing prophylactic supraclavicular irradiation. This exclusion allowed a more reliable evaluation of the impact of IMRT in terms of lung irradiation. In fact, this is obviously higher in the patients irradiated on the supraclavicular region. Incidence of acute skin toxicity (four levels: 0=no toxicity, levels from 1 to 3=toxicity from the first grade to the third grade) was compared among the three adopted techniques (CG, MARA-1, and MARA-2) using the χ2 test. The χ2 test was also performed in order to study the association between the toxicity and the following categorical variables: hypertension, diabetes, smoke, hormone-therapy, chemotherapy (each of them with two levels: 0 no/absence and 1 yes/presence), type of chemotherapy (four levels: 0 no chemotherapy; 1 CMF; 2 anthracycline +/− other drugs (docetaxel excluded); 3 anthracycline+docetaxel +/− other drugs), and haemoglobin (two levels: 0 under the median value, 1 above the median value. For the continuous variables age and PTV, in order to test if mean values differ among the four different levels of acute toxicity, a Kruskal–Wallis test was performed. Aggregating the first two levels (0 and 1) and the second ones (2 and 3) of the toxicity response variable, a new dichotomous variable was considered. The χ2 test between the new variable and each of the above categorical variables was performed, and odds ratios were computed to estimate the risk of experiencing a high level of toxicity (grade equal or greater than 2). For the continuous variables, a univariate logistic regression was performed. For each variable, the reference level was the level with the lowest expected risk of acute toxicity [38]. A multivariable logistic regression was also performed in order to predict if the probability of experiencing a two or three grade of toxicity (level 1) depends on the type of adopted technique, taking into account all the above listed categorical variables as well as age and target volume as covariates. A Forward Stepwise (Wald statistics) procedure was applied in order to obtain a final model including only the subset of variables significant in predicting toxicity. Breast toxicity alone was evaluated because in this study toxicity detected at the level of supraclavicular area was not considered. Differentiation between skin toxicity from breast treatment and from supraclavicular node treatment was shown to be easy. Distinction was simplified by the permanent tattooing performed at the level of the isocenter. According to the technique used, this was placed at the field junction. The analysis of acute toxicity was performed with the RTOG scale [39]. Results Patients A total of 332 patients were studied. Table 1 reports the main characteristics of the studied sample divided into two groups: patients who were treated with the accelerated IMRT-based postoperative radiotherapy (MARA-1, 99 patients; MARA-2, 102 patients), and patients who underwent the “standard” 3D postoperative radiotherapy (CG: 131 patients). The characteristics of radiotherapy and systemic treatment are shown in Table 2. The analyses on the dosimetric variables showed that there was a significant difference between the two treatments with respect to the Dmax, V107%, and Dmin in the PTV. Dmax and V107% were significantly higher in CG than in IMRT: (110.5±9.2 vs 107.3±1.6, respectively, p<0.001 for Dmax; 7.0±6.6 vs 2.4±3.7, respectively, p<0.001 for V107%). A significant improvement of Dmin was observed in patients treated with IMRT: (65.0±17.5 in CG vs 75.4±15.3, p<0.001). No significant differences were recorded in terms of Dmean for ipsilateral lung and heart. Acute toxicity Acute skin toxicity was shown to be significantly associated with the radiotherapy protocol. In particular, patients of MARA-1 study (total dose 44Gy) showed a lower toxicity as compared to CG (total dose 60.4Gy) and to MARA-2 study (total dose 60Gy). The χ2 tests resulted in significant value (p<0.001). The technique MARA-1 presented higher percentages in the cells related to “no toxicity and “grade 1 toxicity” than in the cells related to more serious toxicity. Grade 2 acute skin toxicity was 33.6%, 13.1%, and 45.1% in the CG, MARA-1, and MARA-2, respectively, whereas grade 3 acute skin toxicity was 3.1, 1.0, and 2.0, respectively. The technique with the larger percentage of “no toxicity” was MARA-1. PTV volume increased with increase in degree of acute toxicity (p=0.001): 394.17±117.78 for “no toxicity level”, 498.83±282.57 for “grade 1 toxicity”, 561.32±279.86 for “grade 2 toxicity”, and 871.54±409.48 for “grade 3 toxicity”. A significant relationship (p=0.031) was observed for the age too: younger subjects experienced a higher grade of toxicity (61.84±11.35 for “no toxicity level”, 58.32±11.67 for “grade 1 toxicity”, 55.11±12.75 for “grade 2 toxicity”, and 54.14±8.69 for “grade 3 toxicity”). No other significant correlations with the other parameters analyzed were recorded. When the variable toxicity was recoded as a two-level variable, the associations between the toxicity and chemotherapy (odds ratio: 1.63, p=0.046; the risk for more severe toxicity is more likely in patients treated with chemotherapy) and toxicity and type of chemotherapy resulted in significant value (p=0.040). The risk for more severe toxicity for patients treated with anthracyclines plus docetaxel was 3.77 times the risk for subjects who did not undergo any chemotherapy treatment (p=0.009). Even the association with the protocol resulted in significant value: the use of the MARA-1 protocol decreases the risk of acute toxicity respect to the “standard” 3D protocol (odds ratio=0.28, p=0.0002). Variable PTV resulted in a significant risk factor, whereas age resulted in a protector factor: older subjects had a lower risk of acute toxicity. Results of these univariate analyses are reported in Table 3. All variables were then included in a multivariable logistic regression analyses and odds ratios were computed as well. After applying the Forward Stepwise (Wald Criterion) procedure, to account for multicollinearity, results showed that the probability of more serious toxicity rises if the MARA-2 technique is used with respect to the “standard 3D” procedure, even if the odds ratio (1.47) is not significant: (p=0.16), whereas the use of MARA-1 decreases the risk of acute toxicity. The presence of diabetes (p=0.04) and high values of “volume of PTV” (p=0.01) represent risk factors for more severe toxicity. The odds ratio for patients with diabetes resulted equal to 2.72. Local control With a median follow-up of 31 months (range 5–56months), no patient showed local or regional disease recurrence. Discussion Several published comparisons showed the significant improvement of dosimetric parameters achievable by IMRT, in postoperative radiotherapy of breast carcinoma [9], [10], [17], [25], [40], [41], [42]. However, these studies were dosimetric comparisons between IMRT and standard techniques performed in small groups of 9–17 patients. Our study confirms the finding of improved dose distribution by IMRT in a large unselected population of 332 patients. Obviously, it remains to be seen whether the dosimetric improvement achievable with IMRT will lead to significant clinical outcome improvement. Furthermore, some clinical evaluation of the efficacy of IMRT in reducing toxicity has been recently published [29], [30], [43]. However, these studies focused on the comparison between IMRT and standard techniques in patients treated with standard fractionation schedules. In our study, we evaluated the feasibility of hypofractionated-accelerated treatment by using a simplified IMRT technique. Despite the use of accelerated treatment, and therefore reduced overall treatment time, MARA-2 patients showed acute toxicity similar to CG patients. We can hypothesize that improvement of dosimetric parameters may have contributed to this result. Patients treated in the MARA-1 protocol, despite accelerated treatment, showed a significant reduction of skin acute toxicity; in these patients, reduction of acute toxicity could be related to improvement in dose distribution but also to lower total dose. Postoperative irradiation on breast carcinoma is the most frequent treatment in our division. The use of accelerated-hypofractionated radiotherapy allowed to halve treatment duration (MARA-1) or to decrease it by over 20% (MARA-2 study). Therefore, while being difficult to be quantified, this reduction of treatment duration, definitely improved the accommodation capacity of our unit and reduced waiting times. More generally, the accelerated regimens used in this study can optimize the costs considering the lower fractions/patient ratio. In fact, it is well known that while IMRT increases the costs, both hypofractionation [44] and concomitant boost [25] allow their containment. It should be noted that for MARA-2 study patients, the advantage was not only the shorter treatment duration but also a theoretical better biological efficacy. This stems from the reduced treatment duration and the use of a slightly hypofractionated schedule (2.4Gy to the tumor bed). This is potentially more effective considering that the α/β ratio for breast carcinoma is estimated to be about 4 [31]. Forward planning was used as in most published studies [9], [11], [12], [14], [17], [18], [19], [23], [28]. Inverse planning was less frequently proposed [8], [20], [24], [27]. A study of comparison did not evidence significant differences between the two procedures [22], although an advantage of the second is the possibility to perform simultaneous integrated boosts (SIBs). This technique is in fact associated with a better boost conformation [8], [13]. It is well known that there is an impact of the breast dimensions on the incidence and grade of toxicity [25]. In this sense, our study confirms that the PTV volume is effective in predicting acute toxicity. In order to identify subsets of patients for whom accelerated treatments are not advisable in terms of toxicity, other studies based on late toxicity are necessary. Otherwise, in these subsets of patients, together with accelerated fractionations, alternative techniques of positioning could be tested. These, as prone position, can favour the uniformity of dose distribution [45]. 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a Department of Radiotherapy, “John Paul II” Center for High Technology Research and Education in Biomedical Sciences, Campobasso, Italy b Department of Physics, “John Paul II” Center for High Technology Research and Education in Biomedical Sciences, Campobasso, Italy c Department of Radiotherapy, “Agostino Gemelli”, Policlinico Universitario, Catholic University, Rome, Italy d Department of Gynaecology, “John Paul II” Center for High Technology Research and Education in Biomedical Sciences, Campobasso, Italy e Department of Oncology, General Hospital, Isernia, Italy f Department of Surgery, General Hospital, Isernia, Italy g CNR – Institute of Systems Analysis and Computer Science (IASI), BioMathLab, Rome, Italy h Department of Radiology, “John Paul II” Center for High Technology Research and Education in Biomedical Sciences, Campobasso, Italy i Department of Surgery, “John Paul II” Center for High Technology Research and Education in Biomedical Sciences, Campobasso, Italy  Corresponding author. Address: Department of Oncology, Catholic University-Campobasso, Largo A. Gemelli 1, 86100 Campobasso, Italy.
☆ Presented in part at the ESTRO 27 Congress, Göteborg, Sweden, September 14–18, 2008. PII: S0167-8140(08)00564-1 doi:10.1016/j.radonc.2008.10.017 © 2008 Elsevier Ireland Ltd. All rights reserved. | |
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