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Toxicity and cosmesis following partial breast irradiation consisting of 40 Gy in 10 daily fractions
The Breast 22 (2013) 744e747
Contents lists available at SciVerse ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Toxicity and cosmesis following partial breast irradiation consisting of 40 Gy in 10 daily fractions Marco Trovo a, *, Mario Roncadin a, Jerry Polesel b, Erica Piccoli c, Mario Mileto c, Elvia Micheli d, Tiziana Perin e, Antonino Carbone e, Samuele Massarut c, Mauro G. Trovo a a
Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, via F. Gallini 2, 33081 Aviano (PN), Italy Department of Epidemiology and Biostatistics, Centro di Riferimento Oncologico of Aviano, Italy Department of Surgery, Centro di Riferimento Oncologico of Aviano, Italy d Department of Surgery, Pordenone General Hospital, Italy e Department of Pathology, Centro di Riferimento Oncologico of Aviano, Italy b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 July 2012 Received in revised form 9 October 2012 Accepted 17 December 2012
Purpose: To assess the toxicity and cosmetic results in breast cancer patients undergoing adjuvant partial breast irradiation (PBI) to a total dose of 40 Gy in 10 daily fractions (4 Gy/fraction). Methods and materials: Patients affected by early-stage breast cancer were enrolled in this phase II trial. Patients had to be 60 years old and treated with breast conservative surgery for early stage (pT1eT2 pN0 eN1a) invasive ductal carcinoma. Results: 77 patients were enrolled. Median follow-up was 18 months. The proposed schedule was well tolerated. One patient reported Grade 3 pain at the site of irradiation. Four (5%) patients experience Grade 2 erythema. Late Grade 2 and 1 fibrosis was observed in 3 (4%) and 14 (18%) patients, respectively. Cosmesis was judged “good/excellent” and “poor” in 75 (97%) and in 2 (3%) patients, respectively. Conclusions: 40 Gy in 10 daily fractions, 4 Gy/fraction, is a well tolerated regimen to deliver PBI. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Partial breast irradiation Toxicity Cosmesis Hypofractionation
Introduction In recent years, partial breast irradiation (PBI) has been emerging in the multidisciplinary management of early stage breast cancer after conservative surgery. Treatment of only part of the breast has been justified by the observation that after lumpectomy most recurrences seem to occur in proximity to the primary tumor.1,2 PBI may be performed with a variety of techniques, including intra-operative electron3 or low-energy photon beams,4 interstitial brachytherapy,5 balloon catheters inserted into the tumor bed with afterload radioactive source,6 but that used most often is the three dimensional conformal external beam radiotherapy (3D-CRT) technique, as described by the researchers of the William Beaumont Hospital.7,8 Vicini et al. reported excellent toxicity and cosmesis delivering 38.5 Gy in 3.85 Gy/fraction delivered 2 fractions per day with 3D-CRT, so that this fractionation scheme is now employed in the Radiation Therapy Oncology Group (RTOG) 0413/National Surgical
* Corresponding author. Tel.: þ39 0434 659855; fax: þ39 0434 659524. E-mail address: [email protected] (M. Trovo). 0960-9776/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2012.12.012
Adjuvant Breast Project (NSABP) B-39 trial, a randomized study comparing PBI with whole breast irradiation.9 Although Vicini et al. 8 and numerous other authors have shown that 38.5 Gy in 10 fractions, delivered twice a day in one week, is a well-tolerated regimen, other studies reported unacceptable cosmesis and toxicity adopting the same fractionation. In particular, Jagsi et al. and Hepel et al. documented a remarkably high rate of moderate-to-severe toxicity.10,11 Due to the paucity of clinical data related to the intermediate- and long-term normal tissue effects of this technique, more research seems to be needed to assess the optimal fractionation scheme for PBI. At the beginning of 2009 at the Oncologic Referral Center (CRO) of Aviano a prospective phase 2 study was undertaken to investigate a novel fractionation scheme to deliver PBI, consisting of 40 Gy delivered in 10 daily fractions (4 Gy/fraction). In the present study we report our early and late toxicity results. Materials and methods Between January 2009 and March 2011 patients affected by early stage breast cancer, who had breast conservative surgery were enrolled in this phase 2 prospective study. Both the approval
M. Trovo et al. / The Breast 22 (2013) 744e747
from our institutional review board and written informed consent from the patients were obtained. To be included in this study patients had to be 60 years old and treated with breast conservative surgery for early stage (pT1eT2 pN0eN1a) invasive ductal carcinoma. If stage T2, tumor size had to be 3.5 cm or less. For patients with positive axillary nodes, eligibility was restricted to those with 1e3 positive axillary nodes, who underwent to level IeII axillary dissection. Patients were required to have negative surgical margins; re-excision was allowed in case of positive margin. Patients affected by ductal carcinoma in-situ or invasive lobular carcinoma were not included in this study. All patients underwent sentinel node biopsy at the time of lumpectomy; axillary dissection was performed only in case of sentinel node tumor involvement. Adjuvant hormonal therapy or chemotherapy were allowed. In case of chemotherapy, radiation started one month after the completion of it. Radiation therapy consisted of 40 Gy delivered in 10 daily fractions, 4 Gy/fraction. Treatment volumes and radiation therapy planning were based on NSABP B-39/RTOG 0413 guidelines.9 Treatment planning for radiation was performed by immobilizing patients in supine position with the Quest Breastboard (Q-Fix System). All the patients underwent a complete free-breathing CT simulation to include all the organs at risk (OAR), according to the RTOG 0413 protocol. The CT-simulation was performed not before two weeks following surgery. The clinical target volume (CTV) consisted of the lumpectomy cavity, identified by the post-surgery seroma or by the surgical clips, uniformly expanded by 15 mm, limited to 5 mm from the skin surface and 5 mm from the lunge chest wall interface. The planning target volume (PTV) was calculated from the CTV using uniform 3D expansion of 1 cm. PTV_EVAL is the structure used for dose-volume histogram (DVH) constraints and analysis; it is limited to exclude the part outside the ipsilateral breast and the first 5 mm of tissue under the skin and excluding the PTV expansion beyond the posterior extent of breast tissue. The “uninvolved normal breast” (UNB) was defined as all tissue volume, excluding lung, within the boundaries of standard whole breast tangential fields. Radiation therapy was delivered to the PTV using 3-dimensional conformal fields, adopting the “field within a field” technique to improve dose homogeneity within the PTV and dosimetric coverage, as previously described.12 Dose calculations with tissue inhomogeneity correction were used. All treatments were developed using the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA), using multiple planar and non-coplanar 6-MV photon beams. Dose-volume histograms (DVHs) were generated for all relevant structures for each plan. Specific metrics were chosen to report dosimetric data in terms of PTV dose coverage and dose distribution to the OAR. The Homogeneity Index (HI) was calculated. The HI is defined as the (D2 D98)/mean dose at the PTV_EVAL, where D2 and D98 represent the doses to 2% and 98% of the PTV_EVAL. D98 indicates that at least 98% of the target volume receives this dose, and hence D2 and D98 are considered to be the maximum and minimum doses, respectively. Patients were seen at regular intervals to determine the presence of symptoms, and physicians evaluated toxicity by Common Toxicity Criteria of Adverse Events, version 3.0. Cosmesis was assessed using the Harvard scale. Follow-up visits for the evaluation of toxicity occurred 1, 3, 6 and 12 months from the completion of PBI for the first year, and then once a year. The association between toxicity and categorical patient and treatment characteristics was evaluated by the chi-square frequencies test. Bivariate correlation of continuous variables were assessed using Spearman’s rank correlation. A 5% significance level was considered for the analysis.
745
Results In the study period, 77 patients were enrolled. Patient and tumor characteristics are reported in Table 1. The median follow-up was of 18 months (range, 6e45 months). All patients had a minimum follow-up of 6 months and were assessable for late radiotherapy-related toxicity. The proposed fractionation regimen was well tolerated. One patient reported Grade 3 pain at the site of irradiation 2 months after the end of PBI. Four (5%) patients experience Grade 2 erythema one month after PBI. Eleven (14%) patients had Grade 1 skin toxicity (mild erythema or hyperpigmentation); 15 (19%) patients had Grade 1 subcutaneous toxicity represented by a mild increased density at palpation of the irradiated tissue. Late toxicity was assessable for all the treated patients. Grade 2 and 1 fibrosis was observed in 3 (4%) and 14 (18%) patients, respectively. Two (3%) patient developed a mild hyperpigmentation 6 months after PBI. Three (4%) patients developed asymptomatic fat necrosis. No correlation was found between early and late toxicity and the type of adjuvant systemic therapy (no therapy vs. hormonal therapy vs. chemotherapy). Cosmetic results were judged “good/excellent” in 75 (97%) patients and “poor” in 2 (3%). The mean PTV dimension was 279 ml (range, 134e448 ml) and the mean CTV dimension was 103 ml (range, 46e219 ml). The mean CTV/ipsilateral breast ratio was 0.1 (range, 0.05e0.16); the mean PTV/ipsilateral breast ratio was 0.18 (0.1e0.28). The mean dose covering the 95% (V95%) of the PTV_EVAL was 98% of the prescribed dose (range, 91%e100%). The mean PTV_EVAL dose was 100.8% of the prescribed dose (range, 99%e103%). The mean HI was 0.098 (range, 0.07e0.13). No statistical correlation between dosimetric parameters and toxicity was found. In Table 2 are reported dosimetric data in terms of PTV dose coverage and dose distribution to the OAR. Discussion We reported the toxicity and cosmetic results of a phase 2 prospective study, in which a novel regimen to deliver PBI was
Table 1 Patient and tumor characteristics. Age, years Median Range Tumor dimension, cm Median Range T Stage T1 T2 N Stage N0 N1a Tumor location Upper outer Upper inner Lower outer Lower inner Subareolar Adjuvant therapy Hormonal therapy alone Chemotherapy alone Chemotherapy and hormonal therapy None
69 60e81 2.0 0.5e3.5 69 8 66 11 42 11 7 11 6 50 6 2 19
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Table 2 Dosimetric data. PTV_EVAL V95% Mean PTV_EVAL dose Heart V5% Heart for left located tumors V5% Heart for right located tumors V5% Ipsilateral lung V15% V30% V60% Uninvolved normal breast V100% V50% Controlateral lung V3% Controlateral breast V3% Thyroid V3%
98% 100.8% 2.4% 4.7% 1.3% 17.2% 6.4% 2.5% 11% 38% 1.7% Less than 1% e except in 2 case, due to an unfavorable tumor location Less than 1%
investigated. Such fractionation consisted in 40 Gy delivered in 10 daily fractions, 4 Gy/fraction. This resulted in a well-tolerated regimen: only 1 Grade 3 and 7 Grade 2 toxicity were registered. Fortyeight (62%) patients were free from acute toxicity within 3 months from the completion of PBI, and 60 (78%) of the patients were free from any late effects, including Grade 1 toxicity. These data support the safety of the regimen, although a longer follow-up is needed to further ascertain late toxicity, and in particular late fibrosis. Using the linear quadratic model and the BED equation derived from this model, assuming an a/b ratio of 4 Gy, as suggested by experiments involving irradiation of human breast cancer cell lines, this prescription would be equivalent to 54 Gy in a standard 2-Gy fractionation13,14; if the a/b ratio was assumed to be 3, the prescription would be equivalent to 56 Gy in 2-Gy fraction. These calculations assumed that full repair takes place during the 24-h interval between fractions. In addition, because the hypofractionated regimen also represents an accelerated protocol in which the total dose is delivered in only 10 days, less tumor proliferation is expected to take place compared with that occurring during the standard treatment. Sharing single institution experiences with different irradiation techniques and fractionation schedule seems of major importance, since two recent papers on PBI, published by highly respected groups of experienced investigators, reported unexpected late side effects. Jagsi et al. from the University of Michigan reported that more than 20% of treated patients, using an external beam technique of beamlet intensity modulated radiation therapy (IMRT) with active breathing control, developed unacceptable cosmesis after the radiation therapy course consisting of 38.5 Gy in 10 fractions, delivered twice a day in one week.10 Unacceptable cosmesis was so frequent that the study was closed prematurely. Hepel et al. from Tufts Medical Center and Brown University documented a 10% incidence of moderate-to-severe (Grade3e4) toxicity at a median follow-up of only 18 months.11 The most pronounced late toxicity was subcutaneous fibrosis, that occurred in 25% of patient as Grade 2e4. The overall cosmetic outcome was fair/poor in 18.4% of the patients. Of note, the dose and fractionation schedule used in these two studies are identical to those proposed by the ongoing RTOG 0413/NSABP B-39 randomized trial. Such randomized trial was promoted based on the experience and the data published by the group of William Beaumont Hospital.7
Vicini et al. reported an initial experience on toxicity and cosmetic results in 31 patients treated with PBI with a prescribed dose of 34 or 38.5 Gy in 10 fractions b.i.d.8 With a median followup of 10 months, only 3 (10%) patients experienced a Grade 2 toxicity; no Grade 3 toxicity were reported. Cosmetic results were rated as good/excellent in all evaluable patients. Results with longer follow-up and in a larger cohort of patients were published later: toxicity and cosmesis data were confirmed to be encouraging.15 In a subsequent study, the same authors analyzed the toxicity results of 96 patients treated with accelerated PBI: with a median follow-up of 36 months, only 3% of the patients developed Grade 3 toxicities and 90% of the patients achieved a good/ excellent cosmetic result.16 The RTOG 0319 is a phase I/II study aiming to evaluate the feasibility and toxicity of three-dimensional conformal PBI in a multicenter setting. The technique was determined to be reproducible and the initial results were published in 2005.17 In 2010 the toxicity results of this prospective multinstitutional phase II trial were published.18 Fifty-two patients were evaluable with a median follow-up of 4.5 years. Only 2 (4%) patients developed Grade 3 toxicity: 1 experienced Grade 3 skin fibrosis and teleangectasias, and 1 patient developed Grade 3 radiation dermatitis and myositis. At the same time other authors proposed a different approach to deliver PBI, consisting of daily fraction schedules. Formenti et al. reported the clinical results of 47 patients that were treated in prone position with 3D-CRT.19 PBI consisted of 30 Gy at 6 Gy/fraction, delivered in 5 fractions within 10 days. Acute toxicity was modest, limited to Grade 1e2 erythema. Fourteen of the 47 patients developed Grade 1 late toxicity. Livi et al. reported acute toxicity results of a randomized trial comparing PBI delivered with IMRT vs. conventional fractionated tangential fields to the whole breast.20 A dose of 30 Gy in 5 consecutive fractions at 6 Gy/fraction was prescribed. The tolerance of the PBI schedule was judged excellent, with only 5% Grade 1 and 0.8% Grade 2 acute skin toxicity; no chronic skin damage was observed. The mean PTV/ipsilateral breast ratio of our patients was 0.18, similar to that reported by the other studies in which a 3D-CRT technique was used, while V100% and V50% ipsilateral breast were slightly lower.7,8,19 This was achieved maintaining a high dose coverage and a highly homogeneous dose to the target (mean V95% PTV_EVAL ¼ 98%, mean HI ¼ 0.098). These dosimetric data, including V100% and V50% ipsilateral breast and the HI, might partially explain the good toxicity profile documented in our patients. Our study has some limitations. First, advanced age of patients included in the study (older than 60 years, with a median age of 70 years). We believe that, in this group of patients, cosmesis defects might be underestimated if compared to a younger breast cancer population. Secondly, the toxicity and cosmesis were scored by a single physician, who might have overestimated the clinical outcome. To overcome this limit toxicity and cosmesis results will be assessed independently by two physicians in future studies. Despite these limitations, this study has shown that 40 Gy in 10 daily fractions, 4 Gy/fraction, is a well tolerated regimen to deliver PBI. Longer term follow-up is needed to evaluate whether this hypofractionated regimen is adequate in ensuring an appropriate tumor control in early stage breast cancer patients. Conflict of interest statement All authors disclose any financial and personal relationships with other people or organizations. All authors disclose any study sponsors involvement in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.
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References 1. Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;347:1227e32. 2. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233e41. 3. Orecchia R, Veronesi U. Intraoperative electrons. Semin Radiat Oncol 2005;15: 76e83. 4. Vaidya JS, Joseph DJ, Tobias JS, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. Lancet 2010;376:91e102. 5. Baglan KL, Martinez AA, Frazier RC, et al. The use of high-dose-rate brachytherapy alone after lumpectomy in patients with early-stage breast cancer treated with breast-conserving therapy. Int J Radiat Oncol Biol Phys 2001;50: 1003e11. 6. Keisch M, Vicini F, Kuske RR, et al. Initial clinical experience with the MammoSite breast brachytherapy applicator in women with early-stage breast cancer treated with breast-conserving therapy. Int J Radiat Oncol Biol Phys 2003;55:289e93. 7. Baglan KL, Sharpe MB, Jaffray D, et al. Accelerated partial breast irradiation using 3D conformal radiation therapy (3D-CRT). Int J Radiat Oncol Biol Phys 2003;55:302e11. 8. Vicini F, Remouchamps M, Wallace M, et al. Ongoing clinical experience utilizing 3D conformal external beam radiotherapy to deliver partial breast irradiation in patients with early stage breast cancer treated with breast conserving therapy. Proc Am Soc Radiol Oncol 2003;57:364. 9. http://www.rtog.org/members/protocols/0413/0413.pdf. 10. Jagsi R, Ben-David MA, Moran JM, et al. Unacceptable cosmesis in a protocol investigating intensity-modulated radiotherapy with active breathing control for accelerated partial-breast irradiation. Int J Radiat Oncol Biol Phys 2010;76: 71e8.
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11. Hepel JT, Tokita M, MacAusland SG, et al. Toxicity of three-dimensional conformal radiotherapy for accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 2009;75:1290e6. 12. Trovo M, Sartor G, Chiovati P, et al. Forward intensity modulated radiation therapy for partial breast irradiation confers high dose homogeneity and conformation to the target volume. Int J Radiat Oncol Biol Phys 2010;78: S747. 13. Barendsen GW. Dose fractionation, dose rate and iso-effect relationships for normal tissue responses. Int J Radiat Oncol Biol Phys 1982;8:1981e7. 14. Steel G, Deacon J, Duchesne GM, et al. The dose-rate effect in human tumour cells. Radiother Oncol 1987;9:299e310. 15. Vicini FA, Chen P, Wallace M, et al. Interim cosmetic results and toxicity using 3D conformal external beam radiotherapy to deliver accelerated partial breast irradiation in patients with early-stage breast cancer treated with breastconserving therapy. Int J Radiat Oncol Biol Phys 2007;69:1124e30. 16. Chen P, Gustafson G, Mitchell C, et al. Three-year clinical experience utilizing 3D-conformal radiation therapy to deliver accelerated partial breast irradiation (APBI). Int J Radiat Oncol Biol Phys 2008;72(Suppl.):3. 17. Vicini F, Winter K, Straube W, et al. A phase I/II trial to evaluate threedimensional conformal radiation therapy confined to the region of the lumpectomy cavity for Stage I/II breast carcinoma: Initial report of feasibility and reproducibility of Radiation Therapy Oncology Group (RTOG) Study 0319. Int J Radiat Oncol Biol Phys 2005;63:1531e7. 18. Vicini F, Winter K, Wong J, et al. Initial efficacy results of RTOG 0319: threedimensional conformal radiation therapy (3D-CRT) confined to the region of the lumpectomy cavity for stage I/II breast carcinoma. Int J Radiat Oncol Biol Phys 2010;77:1120e7. 19. Formenti SC, Truong MT, Godberg JD, et al. Prone accelerated partial breast irradiation after breast-conserving surgery: preliminary clinical results and dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 2004;60:493e504. 20. Livi L, Buonamici FB, Simontacchi G, et al. Accelerated partial breast irradiation with IMRT: new technical approach and interim analysis of acute toxicity in a phase III randomized trial. Int J Radiat Oncol Biol Phys 2010;76:978e83.
Contents lists available at SciVerse ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Toxicity and cosmesis following partial breast irradiation consisting of 40 Gy in 10 daily fractions Marco Trovo a, *, Mario Roncadin a, Jerry Polesel b, Erica Piccoli c, Mario Mileto c, Elvia Micheli d, Tiziana Perin e, Antonino Carbone e, Samuele Massarut c, Mauro G. Trovo a a
Department of Radiation Oncology, Centro di Riferimento Oncologico of Aviano, via F. Gallini 2, 33081 Aviano (PN), Italy Department of Epidemiology and Biostatistics, Centro di Riferimento Oncologico of Aviano, Italy Department of Surgery, Centro di Riferimento Oncologico of Aviano, Italy d Department of Surgery, Pordenone General Hospital, Italy e Department of Pathology, Centro di Riferimento Oncologico of Aviano, Italy b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 July 2012 Received in revised form 9 October 2012 Accepted 17 December 2012
Purpose: To assess the toxicity and cosmetic results in breast cancer patients undergoing adjuvant partial breast irradiation (PBI) to a total dose of 40 Gy in 10 daily fractions (4 Gy/fraction). Methods and materials: Patients affected by early-stage breast cancer were enrolled in this phase II trial. Patients had to be 60 years old and treated with breast conservative surgery for early stage (pT1eT2 pN0 eN1a) invasive ductal carcinoma. Results: 77 patients were enrolled. Median follow-up was 18 months. The proposed schedule was well tolerated. One patient reported Grade 3 pain at the site of irradiation. Four (5%) patients experience Grade 2 erythema. Late Grade 2 and 1 fibrosis was observed in 3 (4%) and 14 (18%) patients, respectively. Cosmesis was judged “good/excellent” and “poor” in 75 (97%) and in 2 (3%) patients, respectively. Conclusions: 40 Gy in 10 daily fractions, 4 Gy/fraction, is a well tolerated regimen to deliver PBI. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Partial breast irradiation Toxicity Cosmesis Hypofractionation
Introduction In recent years, partial breast irradiation (PBI) has been emerging in the multidisciplinary management of early stage breast cancer after conservative surgery. Treatment of only part of the breast has been justified by the observation that after lumpectomy most recurrences seem to occur in proximity to the primary tumor.1,2 PBI may be performed with a variety of techniques, including intra-operative electron3 or low-energy photon beams,4 interstitial brachytherapy,5 balloon catheters inserted into the tumor bed with afterload radioactive source,6 but that used most often is the three dimensional conformal external beam radiotherapy (3D-CRT) technique, as described by the researchers of the William Beaumont Hospital.7,8 Vicini et al. reported excellent toxicity and cosmesis delivering 38.5 Gy in 3.85 Gy/fraction delivered 2 fractions per day with 3D-CRT, so that this fractionation scheme is now employed in the Radiation Therapy Oncology Group (RTOG) 0413/National Surgical
* Corresponding author. Tel.: þ39 0434 659855; fax: þ39 0434 659524. E-mail address: [email protected] (M. Trovo). 0960-9776/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2012.12.012
Adjuvant Breast Project (NSABP) B-39 trial, a randomized study comparing PBI with whole breast irradiation.9 Although Vicini et al. 8 and numerous other authors have shown that 38.5 Gy in 10 fractions, delivered twice a day in one week, is a well-tolerated regimen, other studies reported unacceptable cosmesis and toxicity adopting the same fractionation. In particular, Jagsi et al. and Hepel et al. documented a remarkably high rate of moderate-to-severe toxicity.10,11 Due to the paucity of clinical data related to the intermediate- and long-term normal tissue effects of this technique, more research seems to be needed to assess the optimal fractionation scheme for PBI. At the beginning of 2009 at the Oncologic Referral Center (CRO) of Aviano a prospective phase 2 study was undertaken to investigate a novel fractionation scheme to deliver PBI, consisting of 40 Gy delivered in 10 daily fractions (4 Gy/fraction). In the present study we report our early and late toxicity results. Materials and methods Between January 2009 and March 2011 patients affected by early stage breast cancer, who had breast conservative surgery were enrolled in this phase 2 prospective study. Both the approval
M. Trovo et al. / The Breast 22 (2013) 744e747
from our institutional review board and written informed consent from the patients were obtained. To be included in this study patients had to be 60 years old and treated with breast conservative surgery for early stage (pT1eT2 pN0eN1a) invasive ductal carcinoma. If stage T2, tumor size had to be 3.5 cm or less. For patients with positive axillary nodes, eligibility was restricted to those with 1e3 positive axillary nodes, who underwent to level IeII axillary dissection. Patients were required to have negative surgical margins; re-excision was allowed in case of positive margin. Patients affected by ductal carcinoma in-situ or invasive lobular carcinoma were not included in this study. All patients underwent sentinel node biopsy at the time of lumpectomy; axillary dissection was performed only in case of sentinel node tumor involvement. Adjuvant hormonal therapy or chemotherapy were allowed. In case of chemotherapy, radiation started one month after the completion of it. Radiation therapy consisted of 40 Gy delivered in 10 daily fractions, 4 Gy/fraction. Treatment volumes and radiation therapy planning were based on NSABP B-39/RTOG 0413 guidelines.9 Treatment planning for radiation was performed by immobilizing patients in supine position with the Quest Breastboard (Q-Fix System). All the patients underwent a complete free-breathing CT simulation to include all the organs at risk (OAR), according to the RTOG 0413 protocol. The CT-simulation was performed not before two weeks following surgery. The clinical target volume (CTV) consisted of the lumpectomy cavity, identified by the post-surgery seroma or by the surgical clips, uniformly expanded by 15 mm, limited to 5 mm from the skin surface and 5 mm from the lunge chest wall interface. The planning target volume (PTV) was calculated from the CTV using uniform 3D expansion of 1 cm. PTV_EVAL is the structure used for dose-volume histogram (DVH) constraints and analysis; it is limited to exclude the part outside the ipsilateral breast and the first 5 mm of tissue under the skin and excluding the PTV expansion beyond the posterior extent of breast tissue. The “uninvolved normal breast” (UNB) was defined as all tissue volume, excluding lung, within the boundaries of standard whole breast tangential fields. Radiation therapy was delivered to the PTV using 3-dimensional conformal fields, adopting the “field within a field” technique to improve dose homogeneity within the PTV and dosimetric coverage, as previously described.12 Dose calculations with tissue inhomogeneity correction were used. All treatments were developed using the Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA), using multiple planar and non-coplanar 6-MV photon beams. Dose-volume histograms (DVHs) were generated for all relevant structures for each plan. Specific metrics were chosen to report dosimetric data in terms of PTV dose coverage and dose distribution to the OAR. The Homogeneity Index (HI) was calculated. The HI is defined as the (D2 D98)/mean dose at the PTV_EVAL, where D2 and D98 represent the doses to 2% and 98% of the PTV_EVAL. D98 indicates that at least 98% of the target volume receives this dose, and hence D2 and D98 are considered to be the maximum and minimum doses, respectively. Patients were seen at regular intervals to determine the presence of symptoms, and physicians evaluated toxicity by Common Toxicity Criteria of Adverse Events, version 3.0. Cosmesis was assessed using the Harvard scale. Follow-up visits for the evaluation of toxicity occurred 1, 3, 6 and 12 months from the completion of PBI for the first year, and then once a year. The association between toxicity and categorical patient and treatment characteristics was evaluated by the chi-square frequencies test. Bivariate correlation of continuous variables were assessed using Spearman’s rank correlation. A 5% significance level was considered for the analysis.
745
Results In the study period, 77 patients were enrolled. Patient and tumor characteristics are reported in Table 1. The median follow-up was of 18 months (range, 6e45 months). All patients had a minimum follow-up of 6 months and were assessable for late radiotherapy-related toxicity. The proposed fractionation regimen was well tolerated. One patient reported Grade 3 pain at the site of irradiation 2 months after the end of PBI. Four (5%) patients experience Grade 2 erythema one month after PBI. Eleven (14%) patients had Grade 1 skin toxicity (mild erythema or hyperpigmentation); 15 (19%) patients had Grade 1 subcutaneous toxicity represented by a mild increased density at palpation of the irradiated tissue. Late toxicity was assessable for all the treated patients. Grade 2 and 1 fibrosis was observed in 3 (4%) and 14 (18%) patients, respectively. Two (3%) patient developed a mild hyperpigmentation 6 months after PBI. Three (4%) patients developed asymptomatic fat necrosis. No correlation was found between early and late toxicity and the type of adjuvant systemic therapy (no therapy vs. hormonal therapy vs. chemotherapy). Cosmetic results were judged “good/excellent” in 75 (97%) patients and “poor” in 2 (3%). The mean PTV dimension was 279 ml (range, 134e448 ml) and the mean CTV dimension was 103 ml (range, 46e219 ml). The mean CTV/ipsilateral breast ratio was 0.1 (range, 0.05e0.16); the mean PTV/ipsilateral breast ratio was 0.18 (0.1e0.28). The mean dose covering the 95% (V95%) of the PTV_EVAL was 98% of the prescribed dose (range, 91%e100%). The mean PTV_EVAL dose was 100.8% of the prescribed dose (range, 99%e103%). The mean HI was 0.098 (range, 0.07e0.13). No statistical correlation between dosimetric parameters and toxicity was found. In Table 2 are reported dosimetric data in terms of PTV dose coverage and dose distribution to the OAR. Discussion We reported the toxicity and cosmetic results of a phase 2 prospective study, in which a novel regimen to deliver PBI was
Table 1 Patient and tumor characteristics. Age, years Median Range Tumor dimension, cm Median Range T Stage T1 T2 N Stage N0 N1a Tumor location Upper outer Upper inner Lower outer Lower inner Subareolar Adjuvant therapy Hormonal therapy alone Chemotherapy alone Chemotherapy and hormonal therapy None
69 60e81 2.0 0.5e3.5 69 8 66 11 42 11 7 11 6 50 6 2 19
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Table 2 Dosimetric data. PTV_EVAL V95% Mean PTV_EVAL dose Heart V5% Heart for left located tumors V5% Heart for right located tumors V5% Ipsilateral lung V15% V30% V60% Uninvolved normal breast V100% V50% Controlateral lung V3% Controlateral breast V3% Thyroid V3%
98% 100.8% 2.4% 4.7% 1.3% 17.2% 6.4% 2.5% 11% 38% 1.7% Less than 1% e except in 2 case, due to an unfavorable tumor location Less than 1%
investigated. Such fractionation consisted in 40 Gy delivered in 10 daily fractions, 4 Gy/fraction. This resulted in a well-tolerated regimen: only 1 Grade 3 and 7 Grade 2 toxicity were registered. Fortyeight (62%) patients were free from acute toxicity within 3 months from the completion of PBI, and 60 (78%) of the patients were free from any late effects, including Grade 1 toxicity. These data support the safety of the regimen, although a longer follow-up is needed to further ascertain late toxicity, and in particular late fibrosis. Using the linear quadratic model and the BED equation derived from this model, assuming an a/b ratio of 4 Gy, as suggested by experiments involving irradiation of human breast cancer cell lines, this prescription would be equivalent to 54 Gy in a standard 2-Gy fractionation13,14; if the a/b ratio was assumed to be 3, the prescription would be equivalent to 56 Gy in 2-Gy fraction. These calculations assumed that full repair takes place during the 24-h interval between fractions. In addition, because the hypofractionated regimen also represents an accelerated protocol in which the total dose is delivered in only 10 days, less tumor proliferation is expected to take place compared with that occurring during the standard treatment. Sharing single institution experiences with different irradiation techniques and fractionation schedule seems of major importance, since two recent papers on PBI, published by highly respected groups of experienced investigators, reported unexpected late side effects. Jagsi et al. from the University of Michigan reported that more than 20% of treated patients, using an external beam technique of beamlet intensity modulated radiation therapy (IMRT) with active breathing control, developed unacceptable cosmesis after the radiation therapy course consisting of 38.5 Gy in 10 fractions, delivered twice a day in one week.10 Unacceptable cosmesis was so frequent that the study was closed prematurely. Hepel et al. from Tufts Medical Center and Brown University documented a 10% incidence of moderate-to-severe (Grade3e4) toxicity at a median follow-up of only 18 months.11 The most pronounced late toxicity was subcutaneous fibrosis, that occurred in 25% of patient as Grade 2e4. The overall cosmetic outcome was fair/poor in 18.4% of the patients. Of note, the dose and fractionation schedule used in these two studies are identical to those proposed by the ongoing RTOG 0413/NSABP B-39 randomized trial. Such randomized trial was promoted based on the experience and the data published by the group of William Beaumont Hospital.7
Vicini et al. reported an initial experience on toxicity and cosmetic results in 31 patients treated with PBI with a prescribed dose of 34 or 38.5 Gy in 10 fractions b.i.d.8 With a median followup of 10 months, only 3 (10%) patients experienced a Grade 2 toxicity; no Grade 3 toxicity were reported. Cosmetic results were rated as good/excellent in all evaluable patients. Results with longer follow-up and in a larger cohort of patients were published later: toxicity and cosmesis data were confirmed to be encouraging.15 In a subsequent study, the same authors analyzed the toxicity results of 96 patients treated with accelerated PBI: with a median follow-up of 36 months, only 3% of the patients developed Grade 3 toxicities and 90% of the patients achieved a good/ excellent cosmetic result.16 The RTOG 0319 is a phase I/II study aiming to evaluate the feasibility and toxicity of three-dimensional conformal PBI in a multicenter setting. The technique was determined to be reproducible and the initial results were published in 2005.17 In 2010 the toxicity results of this prospective multinstitutional phase II trial were published.18 Fifty-two patients were evaluable with a median follow-up of 4.5 years. Only 2 (4%) patients developed Grade 3 toxicity: 1 experienced Grade 3 skin fibrosis and teleangectasias, and 1 patient developed Grade 3 radiation dermatitis and myositis. At the same time other authors proposed a different approach to deliver PBI, consisting of daily fraction schedules. Formenti et al. reported the clinical results of 47 patients that were treated in prone position with 3D-CRT.19 PBI consisted of 30 Gy at 6 Gy/fraction, delivered in 5 fractions within 10 days. Acute toxicity was modest, limited to Grade 1e2 erythema. Fourteen of the 47 patients developed Grade 1 late toxicity. Livi et al. reported acute toxicity results of a randomized trial comparing PBI delivered with IMRT vs. conventional fractionated tangential fields to the whole breast.20 A dose of 30 Gy in 5 consecutive fractions at 6 Gy/fraction was prescribed. The tolerance of the PBI schedule was judged excellent, with only 5% Grade 1 and 0.8% Grade 2 acute skin toxicity; no chronic skin damage was observed. The mean PTV/ipsilateral breast ratio of our patients was 0.18, similar to that reported by the other studies in which a 3D-CRT technique was used, while V100% and V50% ipsilateral breast were slightly lower.7,8,19 This was achieved maintaining a high dose coverage and a highly homogeneous dose to the target (mean V95% PTV_EVAL ¼ 98%, mean HI ¼ 0.098). These dosimetric data, including V100% and V50% ipsilateral breast and the HI, might partially explain the good toxicity profile documented in our patients. Our study has some limitations. First, advanced age of patients included in the study (older than 60 years, with a median age of 70 years). We believe that, in this group of patients, cosmesis defects might be underestimated if compared to a younger breast cancer population. Secondly, the toxicity and cosmesis were scored by a single physician, who might have overestimated the clinical outcome. To overcome this limit toxicity and cosmesis results will be assessed independently by two physicians in future studies. Despite these limitations, this study has shown that 40 Gy in 10 daily fractions, 4 Gy/fraction, is a well tolerated regimen to deliver PBI. Longer term follow-up is needed to evaluate whether this hypofractionated regimen is adequate in ensuring an appropriate tumor control in early stage breast cancer patients. Conflict of interest statement All authors disclose any financial and personal relationships with other people or organizations. All authors disclose any study sponsors involvement in the study design, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication.
M. Trovo et al. / The Breast 22 (2013) 744e747
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