- Email: [email protected]
Partial Breast Irradiation Delivered With Proton Beam: Results of a Phase II Trial
Original Study
Partial Breast Irradiation Delivered With Proton Beam: Results of a Phase II Trial David A. Bush,1 Jerry D. Slater,1 Carlos Garberoglio,2 Sharon Do,1 Sharon Lum,2 James M. Slater1 Abstract Background and Purpose: A phase II trial sought to determine the safety and efficacy of proton beam irradiation to deliver partial breast radiotherapy after lumpectomy for early-stage breast cancer. Patients and Methods: Eligible patients included women with invasive nonlobular carcinoma ⱕ 3 cm. Surgical therapy included lumpectomy with negative margins and negative axillary lymph nodes on sampling. Postoperative proton radiotherapy to the surgical bed with an additional 1-cm margin was delivered by 40 Gy in 10 fractions over a 2-week course. Patients received systemic therapy as recommended after proton treatment. Patients had clinical evaluations every 6 months and annual mammograms. Results: Fifty patients were enrolled; median follow-up was 48 months. All patients completed the prescribed treatment. Acute toxicities were limited to mild radiation dermatitis. Late skin toxicities included 3 grade 1 telangiectasias. There were no posttreatment infections or ulcerations and no cases of fat necrosis, rib fractures, radiation pneumonitis, or cardiac events. Actuarial 5-year overall survival and disease-free survival rates were 96% and 92%, respectively. No local failures occurred. Ipsilateral breast cancer developed in 1 patient 5.5 years after treatment. Dose-volume histogram analysis showed near-complete elimination of dose to the contralateral breast, lung, and heart. Conclusion: Proton partial breast radiotherapy appeared to be a feasible method of treatment and provided excellent disease control within the ipsilateral breast. Treatment-related toxicity was minimal and no technical limitations prevented treatment delivery. The incidence of posttreatment complications may be less than that reported when using more invasive techniques; comparative trials should be considered. Clinical Breast Cancer, Vol. 11, No. 4, 241-5 © 2011 Published by Elsevier Inc. Keywords: Breast cancer, Complications, Proton, Radiotherapy, Survival
Introduction Whole-breast radiotherapy after lumpectomy for invasive carcinoma of the breast is an established treatment that has been demonstrated to decrease breast cancer recurrence rates and improve disease-specific survival when compared with lumpectomy alone.1,2 Mounting evidence indicates that a subset of these patients may be well treated with target volumes that encompass less than the whole breast. Multiple reports from phase II trials indicate that postoperative radiotherapy directed to only the lumpectomy site may serve as effective treatment to reduce local relapse in a subset of patients.3 1 Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, CA 2 Department of Surgical Oncology, Loma Linda University Medical Center, Loma Linda, CA
Submitted: Nov 11, 2010; Revised: Mar 2, 2011; Accepted: Mar 15, 2011 Address for correspondence: David A. Bush, MD, Loma Linda University Medical Center, Department of Radiation Medicine, 11234 Anderson Street, Loma Linda, CA 92354 Fax: 909-478-4083; e-mail contact: [email protected]
1526-8209/$ - see frontmatter © 2011 Published by Elsevier Inc. doi: 10.1016/j.clbc.2011.03.023
The concept of partial breast irradiation (PBI) is currently being compared with standard whole-breast radiotherapy in multiinstitutional randomized trials. Phase II trials have delivered PBI through multiple different techniques, including interstitial brachytherapy, intracavitary brachytherapy, and photon-based external-beam therapy. Data indicate that disease control within the breast with any of these techniques is excellent. However each of these techniques carries differing rates and types of treatment-related toxicity. Currently there is no agreement as to which technique might be optimal. Brachytherapy approaches are preferred because of their ability to concentrate the radiation dose to the intended target, but they can expose patients to additional surgical complications. External-beam techniques with photons avoid complications of invasive procedures but have lesser ability to limit nontargeted tissues from low and moderate doses of radiotherapy. Proton beam radiotherapy has a distinct advantage compared with photon therapy due to the Bragg peak effect.4 This allows doses of radiation to be delivered to the intended target while minimizing doses given to surrounding healthy tissue. As such, pro-
Clinical Breast Cancer August 2011
241
Partial Breast Irradiation with Proton Beam Figure 1 Isodose Distribution in a Typical Patient. Note the Use of an Oblique Beam to Allow Control of the Skin Dose With Editing of the Aperture Edge
95.0 90.0 80.0 70.0 50.0 30.0
Table 1 Patient Characteristics Age (Years) Mean
63
Range
41-83
Menopausal Status P R
Postmenopausa
45
Premenopausal
4
Perimenopausal
1
Involved Breast Right
27
Left
23
Quadrant UO
35
UI
6
LO
9
Tumor Size
ton beam radiotherapy may be able to provide a noninvasive means of delivering partial breast radiotherapy with an improved safety profile. This article describes the results of a phase II trial investigating the use of proton beam radiotherapy in early-stage breast cancer, treating the lumpectomy site only.
Patients and Methods A phase II protocol was developed and received approval from the Institutional Review Board at Loma Linda University Medical Center and registered as National Clinical Trial NCT00614172. Eligible patients had biopsy-proven invasive carcinoma of the breast; patients with invasive lobular carcinoma were excluded. Patients were required to undergo lumpectomy in which operative margins were pathologically negative by at least 2 mm. Surgical clips were placed in the lumpectomy cavity to aid target volume delineation and treatment delivery. Axillary lymph nodes were evaluated with either a sentinel lymph node biopsy or axillary lymph node dissection. All removed axillary nodes were pathologically negative. Eligible patients had primary tumors that were ⱕ 3 cm in greatest dimension. Patients identified as having extensive ductal carcinoma in situ were excluded. Proton therapy was delivered after completion of surgical therapy and before any systemic treatment. A detailed description of the treatment method has been previously reported.5 Patients were immobilized in the prone position in a custom-made foam mold that immobilized the ipsilateral breast, retracted the contralateral breast, and eliminated respiratory motion. Three-dimensional treatment planning identified the lumpectomy site; an additional 1-cm margin was added to create a clinical target volume (CTV). The CTV could be edited to exclude the chest wall and skin of the breast. In general, 2 to 3 proton beam ports were used to treat patients, with at least 2 fields treated daily. Care was taken to minimize the volume of skin encompassed by the 90% isodose. If necessary, apertures were edited to reduce the skin dose. The most commonly used beam directions were lateral and anterior; oblique beams were used with aperture editing if adequate skin sparing could not be achieved with orthog-
242
Clinical Breast Cancer August 2011
Mean
1.3 cm
Range
0.3-2.8 cm
Stage T1a
4
T1b
22
T1c
17
T2
7
Axillary Sampling SLNB
44
ALND
6
Receptor Status ER⫹
44 (88%)
⫹
35 (70%)
PR
Abbreviations: ALND ⫽ axillary lymph node dissection; ER⫹ ⫽ estrogen positive; LO ⫽ lower outer; PR⫹ ⫽ progesterone positive; SLNB ⫽ sentinel lymph node biopsy; UI ⫽ upper inner; UO ⫽ upper outer.
onal beams as demonstrated in Figure 1. The prescribed dose was 4 Gy given daily for 10 fractions over a 2-week course, with the dose calculated to the isocenter. The 95% isodose line encompassed the entire CTV. After treatment, patients were monitored for toxicity and disease recurrence with clinic evaluations and annual mammograms and chest roentgenograms. Patients received systemic therapy with either chemotherapy or hormonal therapy according to the recommendations of the treating oncologist.
Results Patient Population A total of 50 patients were enrolled and treated in this trial. All patients received the entire course of treatment without delay and all patients were available for evaluation. Table 1 describes patients’ pretreatment characteristics. The average age of the cohort was 63 years, with 45 patients being postmenopausal. The average size of the primary tumor was 1.3 cm, with 24 patients having tumors greater than 1 cm. Forty-four patients had their axillary nodes evaluated with
David A. Bush et al Figure 2 Overall Survival at 5 Years
Table 2 Dose-Volume Histogram Analysis Percent Volume of Structure Receiving Indicated Dose
Mean %
Standard Deviation
V5
49
15
V10
42
14
V20
30
11
V36
12
6
V2
1
2
V5
0
1
V10
0
0
V5
2
2
V10
1
2
V20
1
1
V36
0
0
V5
1
1
V10
0
0
V20
0
0
V36
0
0
Survival (%)
Ipsilateral Breast
Contralateral Breast
100 90 80 70 60 50 40 30 20 10 0
Overall Survival
0
6
12
18
24
30
36
42
48
54
60
38
27
19
16
42
48
54
60
35
25
18
15
Months At Risk 50
50
49
49
48
45
Ipsilateral Lung
Figure 3 Disease-Free Survival at 5 Years Disease-Free Survival
sentinel lymph node biopsy; 6 underwent axillary lymph node sampling. Estrogen receptor status was positive in 88% of patients and progesterone receptor status was positive in 70%.
Survival (%)
Heart (Left Breast Only)
100 90 80 70 60 50 40 30 20 10 0
0
6
12
18
24
30
36
Months At Risk 50
48
47
47
45
42
Dosimetric Analysis All treatment plans were subject to dosimetric review for dose uniformity within the target volumes and dose-volume histogram analysis for all normal tissue regions. Dose uniformity within the CTV was within 5% of the prescribed isocenter dose in all cases. Dose-volume histogram data for normal tissue regions are summarized in Table 2. Ipsilateral breast tissue was contoured from the midline to the midaxilla and included all glandular breast tissue with the exclusion of the volume within the CTV. Dose-volume histogram analysis showed that normal breast tissue was well protected from the high-dose region with an average volume receiving 36 Gy (V36) of 12%. Approximately two thirds of nontargeted breast tissue received doses ⬍ 20 Gy. The skin of the breast was also contoured with a thickness of 3 mm and showed an average V36 of 5%. Minimal or no measurable dose was delivered to the lung, heart, or contralateral breast.
Survival and Patterns of Recurrence The median follow-up time for the study group was 48 months. The actuarial overall and disease-free survival outcomes are shown in Figures 2 and 3. The overall and disease-free survival rates at 5 years were 96% and 92%, respectively. Four patients were found to have recurrent disease during this follow-up period. A new primary breast cancer developed in an adjacent quadrant of the ipsilateral breast 66 months after treatment in 1 patient. There were no other ipsilateral
breast recurrences. Three patients experienced distant metastatic disease between 9 and 25 months after treatment. Metastatic sites included brain, bone, chest wall, and mediastinum. One patient had an isolated axillary recurrence 12 months after treatment; this patient underwent salvage mastectomy followed by systemic therapy and remained disease free as of this writing. One patient died of metastatic breast cancer; 2 others were alive with disease at this writing. One patient was diagnosed with esophageal carcinoma 16 months after completion of treatment.
Toxicity and Cosmesis Acute toxicities were rated according to the National Cancer Institute Common Toxicity Criteria, version 2.0 and are summarized in Table 3. Acute toxicities were limited to cases of radiation dermatitis: 26 patients had grade 1 skin reactions, whereas 4 patients had grade 2 sequelae. No other acute toxicities were observed, and no cases of late toxicity supervened except in 3 patients with grade 1 telangiectasias (Figure 3). There were no cases of skin ulceration or clinical fat necrosis of the breast. During this follow-up period there were no instances of cardiac events, clinical radiation pneumonitis, or rib fractures. All patients underwent a self-assessment of their cosmetic result according to the Harvard method.6 Ninety percent of patients rated their cosmetic result as good or excellent (54% excellent,
Clinical Breast Cancer August 2011
243
Partial Breast Irradiation with Proton Beam Table 3 Treatment Toxicities Toxicity
No.
Acute Skin Grade 1, 2
30
Grade ⱖ3
0
Telangiectasia Grade
13
Grade ⱖ 2
0
Clinical Fat Necrosis
0
Rib Fractures
0
Cardiac Events
0
Breast Infection
0
Pneumonitis Any Grade
0
36% good). Ten percent rated their cosmetic result as fair. There were no self-reported instances of poor cosmetic outcome.
Discussion Partial breast radiotherapy for selected breast cancer patients is supported by multiple phase II trials as well as preliminary reports from randomized phase III trials.7,8 Given the present data, it would seem likely that PBI can be appropriate treatment for selected patients with invasive breast cancer. This study indicates that proton beam radiotherapy for PBI has also demonstrated excellent disease control within the ipsilateral breast and adds to the growing phase II evidence to support this concept. Reports describing PBI have included multiple treatment techniques. The most commonly used methods include interstitial brachytherapy, intracavitary balloon brachytherapy, and photonbased external-beam therapy, including 3-dimensional conformal radiation therapy and intensity-modulated radiation therapy (IMRT). Interstitial brachytherapy was one of the first reported modalities used to deliver PBI and has the most mature results.9-11 Although this method can reduce radiation doses to nontargeted tissues compared with external beam techniques, it requires an invasive procedure; complications can include wound complications and posttreatment infections. The inherently nonuniform dose distribution within the target region leads to areas in which the dose is significantly higher than that prescribed by as much as 50% to 100%.12 It is likely that the physical trauma from interstitial brachytherapy, along with areas of excessive dose, has led to a measurable incidence of fat necrosis within the breast.13 This method of treatment also appears to be limited to a subset of patients because of technical limitations. In a report by Polgar et al, 31% of patients randomized to PBI with interstitial brachytherapy were unable to receive this treatment and were deemed unsuitable for implantation.7 Those patients received external-beam electron therapy. Intracavitary balloon brachytherapy has also been widely used and reported.14,15 As with interstitial brachytherapy, this procedure has been reported to run a risk of wound complications and infections, as well seroma formation and fat necrosis.16 The technique is suitable only for patients
244
Clinical Breast Cancer August 2011
with certain lumpectomy cavity geometries and treatment areas that are sufficiently distant from the skin surface.17 Photon-based external-beam therapy has also been used for PBI and can provide a noninvasive means of delivering relatively uniform dose distributions to targeted areas using 3-dimensional conformal or IMRT techniques.18-20 Although photon treatment methods can lead to better dose uniformity within the targeted area, this outcome is obtained at the expense of increasing volumes of nontargeted tissues to low and moderate doses. At least one recent publication has questioned the adequacy of the cosmetic results with these techniques21; this report has correlated negative cosmetic outcome with increasing dose to the nontargeted breast tissue. Because of the physical dose distribution inherent to photon beams, the capability to reduce the dose to nontargeted breast tissue is limited. Proton beam radiotherapy used for PBI in this trial produced excellent control of disease within the ipsilateral breast. It was able to be applied to all patients enrolled in the trial without any restrictions due to tumor size, location, or geometry. This is due to the fact that beam-shaping methods for proton beam delivery provide a much more flexible treatment delivery than can be given with brachytherapy. The potential for skin toxicity was identified as an area of concern before initiating this trial. Treatment planning techniques were implemented in the study design to keep the 90% isodose within the skin of the breast. Acceptable skin sparing was accomplished by using a unique immobilization system, treating multiple fields per day, using oblique beams when necessary and manually editing apertures during treatment planning when the skin dose was excessive. Although an earlier report found substantial skin reactions when using protons for PBI, treatment planning strategies to minimize skin exposure were not described.22 It appears that skin complications may be minimized by following techniques to minimize the skin dose as used in this trial. The lack of clinical fat necrosis seems to compare favorably with other reports using brachytherapy, likely owing to the elimination of overirradiated areas inherent to brachytherapy procedures. Proton beam radiotherapy can significantly reduce the volume of nontarget tissues exposed to radiation when compared with photon-based treatments. The ipsilateral breast dose with a proton beam appears to be significantly lower than that commonly reported with photon techniques; this has been demonstrated in 3 treatment planning comparisons.5,23,24 Increasing doses to the ipsilateral breast have been correlated with reduced cosmetic outcomes.21 We could expect better outcomes with proton treatment owing to its ability to limit this exposure. The total dose and fractionation schedule chosen for this study comes primarily from published data of other trials of PBI. Nearly all have used a hypofractionated schedule and have been reviewed by Theberge et al.25 The most commonly used schedule for external beam treatment is 38.5 Gy given in 10 fractions over 5 treatment days, and this is the schedule being studied in a national cooperative group randomized trial. Using the linear quadratic model, assuming an ␣/ of 10, the biologic equivalent dose (BED) of this regimen is 53.3 Gy. This is essentially equivalent to a typical whole-breast dose of 45 Gy (BED, 53.1 Gy) but is substantially less if the tumor bed were boosted to 60 Gy (BED, 70.8 Gy). The dose schedule chosen for our study delivers a BED of 56 Gy, slightly higher than the national trial regimen. Treatment was delivered once daily because
David A. Bush et al there does not seem to be a biologic need for hyperfractionation and it eliminates the need for patients to come for treatment multiple times per day. The primary disadvantage of using proton therapy for partial breast treatment may be its limited availability. When this trial was initiated there were 2 centers in the United States capable of treating patients in this fashion. There are now 6 centers in clinical operation and multiple others under construction or in the planning stages. The main obstacle to new centers has been the significant cost to install a new facility. As with most new technologies these costs have decreased with time, which should allow more centers to evaluate new methods of cancer treatment using proton beams. Results of this study appear to indicate that proton beam radiotherapy can be used to effectively deliver PBI in selected patients. It proved to be a highly flexible and customizable therapy that could adequately deliver treatment to patients with primary tumors of any configuration and location within the breast with no case being technically untreatable. The side effect profile was excellent and may reduce certain complications associated with invasive techniques, such as skin ulceration, fat necrosis, and infections that have been consistently reported with brachytherapy. This would need to be confirmed in comparative trials. We believe that the use of proton beam radiotherapy for PBI is promising and we plan to continue and expand its use in the treatment of patients with invasive breast cancer with additional clinical trials.
Acknowledgments The authors with to thank William Preston, EdD, Sandra Teichman, RN, BSN, and Margaret Lunt, RN, BSN, for editing and writing assistance, coordination of manuscript, and data collection, respectively. This work received financial support from the James M. Slater Endowed Chair and the David and Linda Shaheen Foundation.
Disclosure All authors report no relevant relationships to disclose.
References 1. Van de Steene J, Vinh-Hung V, Cutuli B, et al. Adjuvant radiotherapy for breast cancer: effects of longer follow-up. Radiother Oncol 2004; 72:35-43. 2. Early Breast Cancer Trialists Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomized trials. Lancet 2005; 366:2087-2106. 3. Smith BD, Arthur DW, Buchholz TA, et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys 2009; 74:987-1001.
4. Miller DW. A review of proton beam radiation therapy. Med Phys 1995; 22: 1943-54. 5. Bush DA, Slater JD, Garberoglio C, et al. A technique of partial breast irradiation utilizing proton beam radiotherapy: comparison with conformal x-ray therapy. Cancer J 2007; 13:114-8. 6. Rose MA, Olivotto I, Cady B, et al. Conservative surgery and radiation therapy for early breast cancer. Long-term cosmetic results. Arch Surg 1989; 124:153-7. 7. Polgar C, Fodor J, Major T, et al. Breast-conserving treatment with partial or whole breast irradiation for low-risk invasive breast carcinoma—5-year results of a randomized trial. Int J Radiat Oncol Biol Phys 2007; 69:694-702. 8. 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 clinical trial. Int J Radiat Oncol Biol Phys 2009; 77:1-7. 9. Chen PY, Vicini FA, Benitez P, et al. Long-term cosmetic results and toxicity after accelerated partial-breast irradiation: a method of radiation delivery by interstitial brachytherapy for the treatment of early-stage breast carcinoma. Cancer 2006; 106: 991-9. 10. Benitiz PR, Chen PY, Vicini FA, et al. Partial breast irradiation in breast conserving therapy by way of interstitial brachytherapy. Am J Surg 2004; 188:355-64. 11. Kuske RR, Winter K, Arthur DW, et al. Phase II trial of brachytherapy alone after lumpectomy for select breast cancer: Toxicity analysis of RTOG 95-17. Int J Radiat Oncol Biol Phys 2006; 65:45-51. 12. Major T, Frohlich G, Lovey K, et al. Dosimetric experience with accelerated partial breast irradiation using image-guided interstitial brachytherapy. Radiother Oncol 2009; 90:48-55. 13. Wazer DE, Lowther D, Boyle T, et al. Clinically evident fat necrosis in women treated with high-dose-rate brachytherapy alone for early-stage breast cancer. Int J Radiat Oncol Biol Phys 2001; 50:107-11. 14. Benitez PR, Keisch ME, Vicini F, et al. Five-year results: the initial clinical trial of MammoSite balloon brachytherapy for partial breast irradiation in early-stage breast cancer. Am J Surg 2007; 194:456-62. 15. Vicini F, Beitsch PD, Quiet CA, et al. Three-year analysis of treatment efficacy, cosmesis, and toxicity by the American Society of Breast Surgeons MammoSite Breast Brachytherapy Registry Trial in patients treated with accelerated partial breast irradiation (APBI). Cancer 2008; 112:758-66. 16. Nelson JC, Beitsch PD, Vicini FA, et al. Four-year clinical update from the American Society Surgeons MammoSite brachytherapy trial. Am J Surg 2009; 198:83-91. 17. Chen PY, Vicini FA. Partial breast irradiation. Patient selection, guidelines for treatment, and current results. Front Radiat Ther Oncol 2007; 40:253-71. 18. 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 breast-conserving therapy. Int J Radiat Oncol Biol Phys 2007; 69:1124-30. 19. 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; 55:302-11. 20. Rusthoven KE, Carter DL, Howell K, et al. Accelerated partial-breast intensitymodulated radiotherapy results in improved dose distribution when compared with three-dimensional treatment-planning techniques. Int J Radiat Oncol Biol Phys 2008; 70:296-302. 21. 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; 76:71-8. 22. Kozak KR, Smith BL, Adams J, et al. Int J Radiat Oncol Biol Phys 2006; 66:691-8. 23. Moon SH, Shin KH, Kim TH, et al. Dosimetric comparison of four different external beam partial breast irradiation techniques: three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, helical tomotherapy, and proton beam therapy. Radiother Oncol 2009; 90:66-73. 24. Wang X, Amos RA, Zhang X, et al. External-beam accelerated partial breast irradiation using multiple proton beam configurations. Int J Radiat Oncol Biol Phys, 2010 Aug 12 [Epub ahead of print]. 25. Theberge V, Whelan T, Shaitelman SF, et al. Altered fractionation: rationale and justification for whole and partial breast hypofractionated radiotherapy. Semin Radiat Oncol 2011; 21:55-65.
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Partial Breast Irradiation Delivered With Proton Beam: Results of a Phase II Trial David A. Bush,1 Jerry D. Slater,1 Carlos Garberoglio,2 Sharon Do,1 Sharon Lum,2 James M. Slater1 Abstract Background and Purpose: A phase II trial sought to determine the safety and efficacy of proton beam irradiation to deliver partial breast radiotherapy after lumpectomy for early-stage breast cancer. Patients and Methods: Eligible patients included women with invasive nonlobular carcinoma ⱕ 3 cm. Surgical therapy included lumpectomy with negative margins and negative axillary lymph nodes on sampling. Postoperative proton radiotherapy to the surgical bed with an additional 1-cm margin was delivered by 40 Gy in 10 fractions over a 2-week course. Patients received systemic therapy as recommended after proton treatment. Patients had clinical evaluations every 6 months and annual mammograms. Results: Fifty patients were enrolled; median follow-up was 48 months. All patients completed the prescribed treatment. Acute toxicities were limited to mild radiation dermatitis. Late skin toxicities included 3 grade 1 telangiectasias. There were no posttreatment infections or ulcerations and no cases of fat necrosis, rib fractures, radiation pneumonitis, or cardiac events. Actuarial 5-year overall survival and disease-free survival rates were 96% and 92%, respectively. No local failures occurred. Ipsilateral breast cancer developed in 1 patient 5.5 years after treatment. Dose-volume histogram analysis showed near-complete elimination of dose to the contralateral breast, lung, and heart. Conclusion: Proton partial breast radiotherapy appeared to be a feasible method of treatment and provided excellent disease control within the ipsilateral breast. Treatment-related toxicity was minimal and no technical limitations prevented treatment delivery. The incidence of posttreatment complications may be less than that reported when using more invasive techniques; comparative trials should be considered. Clinical Breast Cancer, Vol. 11, No. 4, 241-5 © 2011 Published by Elsevier Inc. Keywords: Breast cancer, Complications, Proton, Radiotherapy, Survival
Introduction Whole-breast radiotherapy after lumpectomy for invasive carcinoma of the breast is an established treatment that has been demonstrated to decrease breast cancer recurrence rates and improve disease-specific survival when compared with lumpectomy alone.1,2 Mounting evidence indicates that a subset of these patients may be well treated with target volumes that encompass less than the whole breast. Multiple reports from phase II trials indicate that postoperative radiotherapy directed to only the lumpectomy site may serve as effective treatment to reduce local relapse in a subset of patients.3 1 Department of Radiation Medicine, Loma Linda University Medical Center, Loma Linda, CA 2 Department of Surgical Oncology, Loma Linda University Medical Center, Loma Linda, CA
Submitted: Nov 11, 2010; Revised: Mar 2, 2011; Accepted: Mar 15, 2011 Address for correspondence: David A. Bush, MD, Loma Linda University Medical Center, Department of Radiation Medicine, 11234 Anderson Street, Loma Linda, CA 92354 Fax: 909-478-4083; e-mail contact: [email protected]
1526-8209/$ - see frontmatter © 2011 Published by Elsevier Inc. doi: 10.1016/j.clbc.2011.03.023
The concept of partial breast irradiation (PBI) is currently being compared with standard whole-breast radiotherapy in multiinstitutional randomized trials. Phase II trials have delivered PBI through multiple different techniques, including interstitial brachytherapy, intracavitary brachytherapy, and photon-based external-beam therapy. Data indicate that disease control within the breast with any of these techniques is excellent. However each of these techniques carries differing rates and types of treatment-related toxicity. Currently there is no agreement as to which technique might be optimal. Brachytherapy approaches are preferred because of their ability to concentrate the radiation dose to the intended target, but they can expose patients to additional surgical complications. External-beam techniques with photons avoid complications of invasive procedures but have lesser ability to limit nontargeted tissues from low and moderate doses of radiotherapy. Proton beam radiotherapy has a distinct advantage compared with photon therapy due to the Bragg peak effect.4 This allows doses of radiation to be delivered to the intended target while minimizing doses given to surrounding healthy tissue. As such, pro-
Clinical Breast Cancer August 2011
241
Partial Breast Irradiation with Proton Beam Figure 1 Isodose Distribution in a Typical Patient. Note the Use of an Oblique Beam to Allow Control of the Skin Dose With Editing of the Aperture Edge
95.0 90.0 80.0 70.0 50.0 30.0
Table 1 Patient Characteristics Age (Years) Mean
63
Range
41-83
Menopausal Status P R
Postmenopausa
45
Premenopausal
4
Perimenopausal
1
Involved Breast Right
27
Left
23
Quadrant UO
35
UI
6
LO
9
Tumor Size
ton beam radiotherapy may be able to provide a noninvasive means of delivering partial breast radiotherapy with an improved safety profile. This article describes the results of a phase II trial investigating the use of proton beam radiotherapy in early-stage breast cancer, treating the lumpectomy site only.
Patients and Methods A phase II protocol was developed and received approval from the Institutional Review Board at Loma Linda University Medical Center and registered as National Clinical Trial NCT00614172. Eligible patients had biopsy-proven invasive carcinoma of the breast; patients with invasive lobular carcinoma were excluded. Patients were required to undergo lumpectomy in which operative margins were pathologically negative by at least 2 mm. Surgical clips were placed in the lumpectomy cavity to aid target volume delineation and treatment delivery. Axillary lymph nodes were evaluated with either a sentinel lymph node biopsy or axillary lymph node dissection. All removed axillary nodes were pathologically negative. Eligible patients had primary tumors that were ⱕ 3 cm in greatest dimension. Patients identified as having extensive ductal carcinoma in situ were excluded. Proton therapy was delivered after completion of surgical therapy and before any systemic treatment. A detailed description of the treatment method has been previously reported.5 Patients were immobilized in the prone position in a custom-made foam mold that immobilized the ipsilateral breast, retracted the contralateral breast, and eliminated respiratory motion. Three-dimensional treatment planning identified the lumpectomy site; an additional 1-cm margin was added to create a clinical target volume (CTV). The CTV could be edited to exclude the chest wall and skin of the breast. In general, 2 to 3 proton beam ports were used to treat patients, with at least 2 fields treated daily. Care was taken to minimize the volume of skin encompassed by the 90% isodose. If necessary, apertures were edited to reduce the skin dose. The most commonly used beam directions were lateral and anterior; oblique beams were used with aperture editing if adequate skin sparing could not be achieved with orthog-
242
Clinical Breast Cancer August 2011
Mean
1.3 cm
Range
0.3-2.8 cm
Stage T1a
4
T1b
22
T1c
17
T2
7
Axillary Sampling SLNB
44
ALND
6
Receptor Status ER⫹
44 (88%)
⫹
35 (70%)
PR
Abbreviations: ALND ⫽ axillary lymph node dissection; ER⫹ ⫽ estrogen positive; LO ⫽ lower outer; PR⫹ ⫽ progesterone positive; SLNB ⫽ sentinel lymph node biopsy; UI ⫽ upper inner; UO ⫽ upper outer.
onal beams as demonstrated in Figure 1. The prescribed dose was 4 Gy given daily for 10 fractions over a 2-week course, with the dose calculated to the isocenter. The 95% isodose line encompassed the entire CTV. After treatment, patients were monitored for toxicity and disease recurrence with clinic evaluations and annual mammograms and chest roentgenograms. Patients received systemic therapy with either chemotherapy or hormonal therapy according to the recommendations of the treating oncologist.
Results Patient Population A total of 50 patients were enrolled and treated in this trial. All patients received the entire course of treatment without delay and all patients were available for evaluation. Table 1 describes patients’ pretreatment characteristics. The average age of the cohort was 63 years, with 45 patients being postmenopausal. The average size of the primary tumor was 1.3 cm, with 24 patients having tumors greater than 1 cm. Forty-four patients had their axillary nodes evaluated with
David A. Bush et al Figure 2 Overall Survival at 5 Years
Table 2 Dose-Volume Histogram Analysis Percent Volume of Structure Receiving Indicated Dose
Mean %
Standard Deviation
V5
49
15
V10
42
14
V20
30
11
V36
12
6
V2
1
2
V5
0
1
V10
0
0
V5
2
2
V10
1
2
V20
1
1
V36
0
0
V5
1
1
V10
0
0
V20
0
0
V36
0
0
Survival (%)
Ipsilateral Breast
Contralateral Breast
100 90 80 70 60 50 40 30 20 10 0
Overall Survival
0
6
12
18
24
30
36
42
48
54
60
38
27
19
16
42
48
54
60
35
25
18
15
Months At Risk 50
50
49
49
48
45
Ipsilateral Lung
Figure 3 Disease-Free Survival at 5 Years Disease-Free Survival
sentinel lymph node biopsy; 6 underwent axillary lymph node sampling. Estrogen receptor status was positive in 88% of patients and progesterone receptor status was positive in 70%.
Survival (%)
Heart (Left Breast Only)
100 90 80 70 60 50 40 30 20 10 0
0
6
12
18
24
30
36
Months At Risk 50
48
47
47
45
42
Dosimetric Analysis All treatment plans were subject to dosimetric review for dose uniformity within the target volumes and dose-volume histogram analysis for all normal tissue regions. Dose uniformity within the CTV was within 5% of the prescribed isocenter dose in all cases. Dose-volume histogram data for normal tissue regions are summarized in Table 2. Ipsilateral breast tissue was contoured from the midline to the midaxilla and included all glandular breast tissue with the exclusion of the volume within the CTV. Dose-volume histogram analysis showed that normal breast tissue was well protected from the high-dose region with an average volume receiving 36 Gy (V36) of 12%. Approximately two thirds of nontargeted breast tissue received doses ⬍ 20 Gy. The skin of the breast was also contoured with a thickness of 3 mm and showed an average V36 of 5%. Minimal or no measurable dose was delivered to the lung, heart, or contralateral breast.
Survival and Patterns of Recurrence The median follow-up time for the study group was 48 months. The actuarial overall and disease-free survival outcomes are shown in Figures 2 and 3. The overall and disease-free survival rates at 5 years were 96% and 92%, respectively. Four patients were found to have recurrent disease during this follow-up period. A new primary breast cancer developed in an adjacent quadrant of the ipsilateral breast 66 months after treatment in 1 patient. There were no other ipsilateral
breast recurrences. Three patients experienced distant metastatic disease between 9 and 25 months after treatment. Metastatic sites included brain, bone, chest wall, and mediastinum. One patient had an isolated axillary recurrence 12 months after treatment; this patient underwent salvage mastectomy followed by systemic therapy and remained disease free as of this writing. One patient died of metastatic breast cancer; 2 others were alive with disease at this writing. One patient was diagnosed with esophageal carcinoma 16 months after completion of treatment.
Toxicity and Cosmesis Acute toxicities were rated according to the National Cancer Institute Common Toxicity Criteria, version 2.0 and are summarized in Table 3. Acute toxicities were limited to cases of radiation dermatitis: 26 patients had grade 1 skin reactions, whereas 4 patients had grade 2 sequelae. No other acute toxicities were observed, and no cases of late toxicity supervened except in 3 patients with grade 1 telangiectasias (Figure 3). There were no cases of skin ulceration or clinical fat necrosis of the breast. During this follow-up period there were no instances of cardiac events, clinical radiation pneumonitis, or rib fractures. All patients underwent a self-assessment of their cosmetic result according to the Harvard method.6 Ninety percent of patients rated their cosmetic result as good or excellent (54% excellent,
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Partial Breast Irradiation with Proton Beam Table 3 Treatment Toxicities Toxicity
No.
Acute Skin Grade 1, 2
30
Grade ⱖ3
0
Telangiectasia Grade
13
Grade ⱖ 2
0
Clinical Fat Necrosis
0
Rib Fractures
0
Cardiac Events
0
Breast Infection
0
Pneumonitis Any Grade
0
36% good). Ten percent rated their cosmetic result as fair. There were no self-reported instances of poor cosmetic outcome.
Discussion Partial breast radiotherapy for selected breast cancer patients is supported by multiple phase II trials as well as preliminary reports from randomized phase III trials.7,8 Given the present data, it would seem likely that PBI can be appropriate treatment for selected patients with invasive breast cancer. This study indicates that proton beam radiotherapy for PBI has also demonstrated excellent disease control within the ipsilateral breast and adds to the growing phase II evidence to support this concept. Reports describing PBI have included multiple treatment techniques. The most commonly used methods include interstitial brachytherapy, intracavitary balloon brachytherapy, and photonbased external-beam therapy, including 3-dimensional conformal radiation therapy and intensity-modulated radiation therapy (IMRT). Interstitial brachytherapy was one of the first reported modalities used to deliver PBI and has the most mature results.9-11 Although this method can reduce radiation doses to nontargeted tissues compared with external beam techniques, it requires an invasive procedure; complications can include wound complications and posttreatment infections. The inherently nonuniform dose distribution within the target region leads to areas in which the dose is significantly higher than that prescribed by as much as 50% to 100%.12 It is likely that the physical trauma from interstitial brachytherapy, along with areas of excessive dose, has led to a measurable incidence of fat necrosis within the breast.13 This method of treatment also appears to be limited to a subset of patients because of technical limitations. In a report by Polgar et al, 31% of patients randomized to PBI with interstitial brachytherapy were unable to receive this treatment and were deemed unsuitable for implantation.7 Those patients received external-beam electron therapy. Intracavitary balloon brachytherapy has also been widely used and reported.14,15 As with interstitial brachytherapy, this procedure has been reported to run a risk of wound complications and infections, as well seroma formation and fat necrosis.16 The technique is suitable only for patients
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with certain lumpectomy cavity geometries and treatment areas that are sufficiently distant from the skin surface.17 Photon-based external-beam therapy has also been used for PBI and can provide a noninvasive means of delivering relatively uniform dose distributions to targeted areas using 3-dimensional conformal or IMRT techniques.18-20 Although photon treatment methods can lead to better dose uniformity within the targeted area, this outcome is obtained at the expense of increasing volumes of nontargeted tissues to low and moderate doses. At least one recent publication has questioned the adequacy of the cosmetic results with these techniques21; this report has correlated negative cosmetic outcome with increasing dose to the nontargeted breast tissue. Because of the physical dose distribution inherent to photon beams, the capability to reduce the dose to nontargeted breast tissue is limited. Proton beam radiotherapy used for PBI in this trial produced excellent control of disease within the ipsilateral breast. It was able to be applied to all patients enrolled in the trial without any restrictions due to tumor size, location, or geometry. This is due to the fact that beam-shaping methods for proton beam delivery provide a much more flexible treatment delivery than can be given with brachytherapy. The potential for skin toxicity was identified as an area of concern before initiating this trial. Treatment planning techniques were implemented in the study design to keep the 90% isodose within the skin of the breast. Acceptable skin sparing was accomplished by using a unique immobilization system, treating multiple fields per day, using oblique beams when necessary and manually editing apertures during treatment planning when the skin dose was excessive. Although an earlier report found substantial skin reactions when using protons for PBI, treatment planning strategies to minimize skin exposure were not described.22 It appears that skin complications may be minimized by following techniques to minimize the skin dose as used in this trial. The lack of clinical fat necrosis seems to compare favorably with other reports using brachytherapy, likely owing to the elimination of overirradiated areas inherent to brachytherapy procedures. Proton beam radiotherapy can significantly reduce the volume of nontarget tissues exposed to radiation when compared with photon-based treatments. The ipsilateral breast dose with a proton beam appears to be significantly lower than that commonly reported with photon techniques; this has been demonstrated in 3 treatment planning comparisons.5,23,24 Increasing doses to the ipsilateral breast have been correlated with reduced cosmetic outcomes.21 We could expect better outcomes with proton treatment owing to its ability to limit this exposure. The total dose and fractionation schedule chosen for this study comes primarily from published data of other trials of PBI. Nearly all have used a hypofractionated schedule and have been reviewed by Theberge et al.25 The most commonly used schedule for external beam treatment is 38.5 Gy given in 10 fractions over 5 treatment days, and this is the schedule being studied in a national cooperative group randomized trial. Using the linear quadratic model, assuming an ␣/ of 10, the biologic equivalent dose (BED) of this regimen is 53.3 Gy. This is essentially equivalent to a typical whole-breast dose of 45 Gy (BED, 53.1 Gy) but is substantially less if the tumor bed were boosted to 60 Gy (BED, 70.8 Gy). The dose schedule chosen for our study delivers a BED of 56 Gy, slightly higher than the national trial regimen. Treatment was delivered once daily because
David A. Bush et al there does not seem to be a biologic need for hyperfractionation and it eliminates the need for patients to come for treatment multiple times per day. The primary disadvantage of using proton therapy for partial breast treatment may be its limited availability. When this trial was initiated there were 2 centers in the United States capable of treating patients in this fashion. There are now 6 centers in clinical operation and multiple others under construction or in the planning stages. The main obstacle to new centers has been the significant cost to install a new facility. As with most new technologies these costs have decreased with time, which should allow more centers to evaluate new methods of cancer treatment using proton beams. Results of this study appear to indicate that proton beam radiotherapy can be used to effectively deliver PBI in selected patients. It proved to be a highly flexible and customizable therapy that could adequately deliver treatment to patients with primary tumors of any configuration and location within the breast with no case being technically untreatable. The side effect profile was excellent and may reduce certain complications associated with invasive techniques, such as skin ulceration, fat necrosis, and infections that have been consistently reported with brachytherapy. This would need to be confirmed in comparative trials. We believe that the use of proton beam radiotherapy for PBI is promising and we plan to continue and expand its use in the treatment of patients with invasive breast cancer with additional clinical trials.
Acknowledgments The authors with to thank William Preston, EdD, Sandra Teichman, RN, BSN, and Margaret Lunt, RN, BSN, for editing and writing assistance, coordination of manuscript, and data collection, respectively. This work received financial support from the James M. Slater Endowed Chair and the David and Linda Shaheen Foundation.
Disclosure All authors report no relevant relationships to disclose.
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