Five Year Outcome of 145 Patients With Ductal Carcinoma In Situ (DCIS) After Accelerated Breast Radiotherapy

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1 International Journal of Radiation Oncology biology physics Clinical Investigation: Breast Cancer Five Year Outcome of 145 Patients With Ductal Carcinoma In Situ (DCIS) After Accelerated Breast Radiotherapy Raquel Ciervide, M.D.,* Shubhada Dhage, M.D., y Amber Guth, M.D., y Richard L. Shapiro, M.D., y Deborah M. Axelrod, M.D., y Daniel F. Roses, M.D., y and Silvia C. Formenti, M.D.* Departments of *Radiation Oncology and y Surgery, New York University School of Medicine, NYU Langone Medical Center, New York, New York Received Aug 29, 2011, and in revised form Nov 3, Accepted for publication Nov 3, 2011 Summary In invasive breast cancer, several strategies have been employed to reduce the overall treatment time by using accelerated treatment schedules. Although wellestablished for invasive breast cancer, this approach has only recently emerged for DCIS. To test hypofractionation regimens of radiotherapy after breast conservation surgery in DCIS patients, we conducted 2 consecutive trials of accelerated whole-breast radiotherapy. This report summarizes our experience in 145 patients with a median follow-up of 5 years and demonstrates a DCIS recurrence in 6 (4.1%), without any invasive cancers. Background: Accelerated whole-breast radiotherapy (RT) with tumor bed boost in the treatment of early invasive breast cancer has demonstrated equivalent local control and cosmesis when compared with standard RT. Its efficacy in the treatment of ductal carcinoma in situ (DCIS) remains unknown. Methods and Materials: Patients treated for DCIS with lumpectomy and negative margins were eligible for 2 consecutive hypofractionated whole-breast RT clinical trials. The first trial (New York University [NYU] 01-51) prescribed to the whole breast 42 Gy (2.8 Gy in 15 fractions) and the second trial (NYU ) 40.5 Gy (2.7 Gy in 15 fractions) with an additional daily boost of 0.5 Gy to the surgical cavity. Results: Between 2002 and 2009, 145 DCIS patients accrued, 59 to the first protocol and 86 to the second trial. Median age was 56 years and 65% were postmenopausal at the time of treatment. Based on optimal sparing of normal tissue, 79% of the patients were planned and treated prone and 21% supine. At 5 years median follow-up (60 months; range months), 6 patients (4.1%) experienced an ipsilateral breast recurrence in all cases of DCIS histology. In 3/6 patients, recurrence occurred at the original site of DCIS and in the remaining 3 cases outside the original tumor bed. New contralateral breast cancers arose in 3 cases (1 DCIS and 2 invasive carcinomas). Cosmetic self-assessment at least 2 years after treatment is available in 125 patients: 91% reported good-to-excellent and 9% reported fair-to-poor outcomes. Conclusions: With a median follow-up of 5 years, the ipsilateral local recurrence rate is 4.1%, comparable to that reported from the NSABP (National Surgical Adjuvant Breast and Bowel Project) trials that employed 50 Gy in 25 fractions of radiotherapy for DCIS. There were no invasive recurrences. These results provide preliminary evidence that accelerated hypofractionated external beam radiotherapy is a viable option for DCIS. Ó 2012 Elsevier Inc. Reprint requests to: Silvia C. Formenti, M.D., Department of Radiation Oncology, 160 E 34th St, New York, NY Tel: (212) ; Fax: (212) ; silvia.formenti@nyumc.org Conflict of interest: none. Int J Radiation Oncol Biol Phys, Vol. 83, No. 2, pp. e159ee164, /$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi: /j.ijrobp

2 e160 Ciervide et al. International Journal of Radiation Oncology Biology Physics Introduction Since the introduction of widespread breast screening by mammography in the early 1980s, the detection of ductal carcinoma in situ (DCIS) has increased dramatically from an incidence of 1.87 per 100,000 between 1973 and 1975 to 32.5 in 2004 (1). Four randomized trials and a meta-analysis have shown that after local excision with negative margins, irradiation substantially reduces the risk of recurrence of both invasive and in situ carcinoma (2e5). The addition of tamoxifen further enhances the protective effect of radiotherapy and reduces the incidence of new contralateral cancers (7). Therefore, the current standard treatment remains breast-conserving surgery followed by 5-6 weeks of adjuvant radiation therapy to the whole breast, generally with antihormonal treatment for carriers of hormone receptor positive tumors. Several strategies have been employed to reduce the overall treatment time by using an accelerated treatment schedule and increasing the dose per fraction of radiotherapy for breast cancer. This approach is well-established for invasive breast cancer (8, 9) and is emerging for DCIS (10e12). To test hypofractionation regimens of radiotherapy after breast-conserving surgery in DCIS patients we studied 2 accelerated treatment regimens. This report summarizes this experience, with a median follow-up of 5 years. Methods Between 2002 and 2009, 2 institutional review boardeapproved accelerated radiotherapy prospective studies, New York University (NYU) ( ) and NYU ( ), were open for accrual to stage 0-2 breast cancer patients. Eligibility required that patients undergo breast-conserving surgery with negative margins (Table 1). Antihormonal therapy was recommended for hormone-positive patients. Radiation therapy was delivered according to the 2 protocols (Table 2). Simulation and planning Patients were first imaged (2.5-mm computed tomography [CT] slice thickness) in the supine position: the borders of the breast field were marked with CT fiducial markers on the skin according to conventional guidelines. Patients were then reimaged prone, on a specially designed prone mattress (US Patent B2) that allowed the indexed breast tissue to fall freely below the table, granting unobstructed access to the radiation ports from multiple beam angles. Details on NYU prone setup were previously reported (13). Briefly, during simulation, a reference transverse plane is identified at the level of the breast areola, on the supine Table 1 NYU protocols Accrual NYU trial period Phase I-II study of hypofractionated adjuvant breast radiation therapy in women with DCIS accelerated intensity-modulated radiation therapy (AIMRT) to the breast after segmental mastectomy: identification of optimal individual positioning Eligibility criteria Pre- or postmenopausal women Original tumor nonpalpable (mammographically detected) ptis, DCIS excised with: 1. Negative margins 2. At least 1 mm 3. No residual microcalcification Grade: Low, intermediate, high (only if unicentric) Unicentric or multicentric Pre- or postmenopausal women Stage 0 (DCIS), I-II breast cancer Biopsy-proven invasive breast cancer, excised with: 1. Negative margins 2. At least 1 mm Status post-segmental mastectomy, after SNB and/or ALND (DCIS and tumors <5 mm do not require nodal assessment) >2 weeks from last chemotherapy Fractionation regimen 3D-CRT 15 fractions (3 weeks) 2.8 Gy/fraction fraction to the index breast (total dose 42 Gy) IMRT 15 fractions (3 weeks) 2.7 Gy/fraction to the index breast (total dose 40.5 Gy) Plus 0.5 Gy daily boost to surgical cavity (total dose 4.8 Gy) No. of patients Position 59 Supine (nz34; 57.62%) Prone (nz25; 42.38%) 86 Supine (nz6; 8.05%) Prone (nz80; 91.95%) Follow-up (months) Median Z Mean Z Median Z Mean Z Median Z 60 Mean Z 60 Abbreviations: ALND Z axillary lymph node dissection; CRT Z conformal radiotherapy; DCIS Z ductal carcinoma in situ; ptis Z Ductal Carcinoma in situ (TNM classification); SNB Z sentinel node biopsy.

3 Volume 83 Number Accelerated whole breast radiotherapy for DCIS: Clinical experience e161 Table 2 Patient and tumor characteristics (NZ145) Patients N (%) Ethnicity White Black Asian 11 8 Hispanic 9 6 Age < > Breast laterality Left Right DCIS grade Low Intermediate High DCIS size (mm) > < < Tumor receptors Estrogen Negative Positive Unknown Progesterone Negative Positive Unknown Antihormonal treatment Tamoxifen Anastrozole 11 8 None Treatment position Supine Prone Abbreviation: DCIS Z ductal carcinoma in situ. position. Three fiducial markers are placed on the same plane, by laser light alignment, on the midline in front of the sternum and on the ipsilateral and contralateral mid-axillary line; the same plane is identified prone. Target definition For each patient, the radiation oncologist contoured the target volumes and normal structures including lung and heart in each set of images from the 2 CT simulations. The superior edge of the field is defined at the inferior margin of the clavicular head. The inferior margin is placed at 2 cm below the inframammary fold. The posterior edge is defined on the reference transverse plane identified by the same radiopaque markers in prone and supine position. A virtual line that connects the sternal marker to a point on the skin of the lateral chest wall, which is just anterior to the edge of the latissimus dorsi muscle, defines the posterior edge of the tangents fields and assures inclusion of the breast tissue in both positions. For protocol , the tumor bed, defined as the postlumpectomy seroma region on CT planning, is expanded by 1.5 cm (13). A volumetric analysis using contouring tools of the Eclipse Treatment Planning System (Varian Medical System, Palo Alto, CA) determined the volumes (percentage and absolute) of the heart and lung included in the treatment fields for either setup. The selection of the optimal treatment plan satisfied the following criteria: 1) inclusion of the breast tissue and tumor bed with at least 1 cm of margin; 2) maximum heart sparing; and 3) maximum lung sparing. For right-breast cancer patients, reducing in-field lung volume dictated selection, whereas for left-breast cancer patients, the optimal treatment plan minimized in-field heart volume. If the in-field heart volume was equivalent in the 2 positions, the setup with the least in-field lung volume was selected. After selection of the optimal setup position, opposed tangent photon beams were used to treat the entire breast with smaller fields targeting the tumor bed with a 1-cm margin via inverse planned IMRT. No multileaf collimators were used to block heart volume within the treatment fields. All patients were followed 3, 6, and 12 months after treatment course, then yearly thereafter. Statistics The cohort of patients was analyzed according to the 2 different radiation NYU protocols. The length of follow-up was calculated from the consent form sign date to the date of the last follow-up in the radiation oncology department. Categorical variables are presented as proportions and continuous variables as means, medians, and ranges. The main outcome was ipsilateral recurrences (as DCIS or invasive). Recurrence-free survival and actuarial recurrence-free survival were calculated with SPSS v Patients were censored for the risk of local recurrence on confirmation of a distant recurrence or death. Results A total of 459 patients accrued to the 2 trials: 145 patients with DCIS were enrolled and constitute the cohort analyzed in this report. Table 2 summarizes patients and tumor characteristics. The median age was 56.4 years (range ) with 57% of the patients being older than 60. At the time of treatment, 65% of patients were postmenopausal, 6% perimenopausal, and 29% premenopausal. There were 76 left-breast and 69 right-breast cancer patients. DCIS was low-grade in 18% of patients, intermediate in 35%, and high-grade in 46%. Median size of the DCIS was 5 mm (range 1-60 mm). Among the 145 patients, 92 patients had estrogen receptor positive (63%) and 65 (45%) estrogen and progesterone receptor positive tumors. Seventy-six percent of the patients were Caucasian, 10% African American, 8% Asian, and 6% Hispanic. Treatment Before radiation, 62 of 145 patients (43%) underwent additional surgery to achieve negative margins. All patients received whole breast treatment. Fifty-nine patients accrued to the first protocol and 86 to the second, which included

4 e162 Ciervide et al. International Journal of Radiation Oncology Biology Physics Table 3 Patient Pattern of local recurrences (6 recurrences /145 patients) RT protocol Original ER status Antihormonal therapy Original quadrant vs. LR site Recurrence pathology (grade) Time to LR (months) LR management 1 WB þ Tamoxifen UOQ/central DCIS Local excision and HT 2 WB þ Tamoxifen (3 yrs ) LOQ/NS DCIS Mastectomy 3 WB þ Tamoxifen LIQ/LIQ DCIS Mastectomy 4 WBþboost þ No UOQ/UOQ DCIS 9.73 Local excision and HT 5 WBþboost þ No UOQ/NS DCIS Mastectomy 6 WBþboost þ No UOQ/UOQ DCIS Biopsy only Abbreviations: DCIS Z ductal carcinoma in situ; HT Z Hormonal Therapy; LIQ Z lower inner quadrant; LOQ Z lower outer quadrant; LR Z Local Recurrence; NS Z non specified; RT Z radiotherapy; UOQ Z upper outer quadrant; WB Z NYU Whole Breast Irradiation; WBþboost Z NYU Whole Breast Irradiation plus Concomitant Boost. a tumor bed boost. Based on maximal sparing of normal tissue, an optimal treatment was selected as described in methods, resulting in 79% of the patients planned and treated prone and 21% supine. After radiation therapy, 63 of 145 patients (43%) received antihormonal therapy (35% tamoxifen, 8% anastrozole). With a median follow-up of 5 years, all patients are alive. Six of the 145 patients (4.1%) developed an ipsilateral breast recurrence (Table 3). New contralateral breast cancers occurred in 3 other cases (1 DCIS and 2 invasive carcinomas), resulting in actuarial DFS of 95%. All ipsilateral breast recurrences were of DCIS histology and occurred in patients whose original tumors were estrogen positive. At 5 years median follow-up none of the 145 patients developed an ipsilateral invasive recurrence of breast cancer. Patterns of recurrence did not vary in the 2 trials and were independent of receiving a radiation boost (3 recurrences in each trial). The 3 patients who recurred in the group receiving a boost, however, were noncompliant in terms of adherence to the prescription of tamoxifen. Three recurrences were in the same quadrant as the primary location, 2 of these in patients accrued to the concomitant boost trial. Recurrences were managed with mastectomy in 3/6 cases, local excision, and hormonal therapy in 2/6. One patient underwent excisional biopsy and refused further treatment. Late toxicity was confined to the skin. Fibrosis was grade 2 in 4% of patients and telangiectasia was grade 2 in 7% and grade 3 in 2% (only grade 3 toxicity). Grade 2 pigmentation changes were detectable in 4% of patients. Breast edema was grade 2 in 6% and grade 2 retraction in 4% of the patients (Table 4). Cosmetic assessment after a minimum of 2 years was available as selfassessment in 125/145 patients: it was good-excellent in the majority 91% and fair-poor in 9% (Table 5). Figure 1 demonstrates a good-excellent cosmetic result and Figure 2 an example of fair-poor cosmesis. Discussion The reported experience of an accelerated hypofractionated scheme of postoperative radiation therapy, independent of the addition of a boost to the tumor bed, suggests that this approach is a feasible option for treatment of DCIS patients. At a median follow-up of 5 years, 6/145 patients developed local recurrences (4.1%): all 6 recurrent cases were DCIS. Randomized trials have demonstrated that after breastconserving therapy and radiotherapy, ipsilateral breast recurrences rates range from 5%-10% at 5 years (2e5). In these studies, however, approximately half of the recurrences were invasive cancers, whereas none of the recurrences in this series were invasive. A recent update of the outcome of 2 large prospective randomized trials, NSABP 17 and 21, confirming the important role of radiotherapy in reducing the risk of local recurrence, demonstrates that patients with DCIS who recurred locally were significantly more likely to die of breast cancers than those who did not recur (14). However, the uncontroversial benefit that radiotherapy conveys in terms of local control has failed to reflect in improved breast cancer survival (14). On the other hand, attempts to prospectively identify a subset of patients that could be safely managed without adjuvant radiation have failed. Despite some retrospective studies suggesting that patients with widely excised small lesions and low- or intermediate-grade histology may achieve comparably low rates of recurrence without the addition of breast irradiation (15), research efforts to identify which subset of DCIS patients can be managed with segmental mastectomy only, without radiotherapy, have generated disappointing results. A prospective, single-arm study examined the role of excision alone in DCIS. Intergroup CE5194, a multi-institutional study, tested whether a more detailed pathologic assessment (involving sequential sectioning of the embedded complete specimen) could Table 4 Late toxicity Late toxicity RTOG grade Grade 0 % Grade 1 % Grade 2 % Grade 3 % Fibrosis Telangiectasia Pigmentation changes Breast edema Retraction Abbreviation: RTOG Z Radiation Therapy Oncology Group.

5 Volume 83 Number Accelerated whole breast radiotherapy for DCIS: Clinical experience e163 Table 5 Cosmesis as assessed at last RT follow-up (NZ127 with at least 24 months follow-up) Cosmesis Patients, N (%) Excellent 60 (47.24%) 115 (90.5%) Good 55 (43.31%) Fair 10 (7.87%) 12 (9.5%) Poor 2 (1.57%) identify a group of DCIS patients who do not require postoperative radiation. Despite the selective eligibility criteria to this trial, with a median follow-up of 6.2 years for the 565 patients accrued, the 5- year rate of an ipsilateral local recurrence was 6.1%. Approximately half of the recurrences in the high-grade group and 35% in the low/intermediate-grade group were of the invasive type (16). Similar results were found when lower-risk DCIS patients were studied in a single institution study that prospectively tested the possibility of omitting radiotherapy after surgery. Eligibility to this trial was limited to carriers of grade 1 or 2 DCIS, with a mammographic size measuring 2.5 cm, after wide surgical excision, with final margins of 1 cm, or after reexcision without residual DCIS. Despite an accrual goal of 200 patients, the study closed early based on prefixed stopping rules because of the observed rate of local recurrence. With a median follow-up of 40 months, 8.2% (13/158) of the patients developed an ipsilateral local recurrence, corresponding to a 5-year rate of 12% (17). A population-based meta-analysis confirmed the effect of radiotherapy on local control and failed to identify which subsets can be safely treated without it after breast conservation therapy (6). The failure to identify a subset of DCIS carriers that can be safely treated by surgery alone sustains the practice of overtreatment of the majority of patients to prevent local recurrence, despite the lack of evidence of an advantage in survival. The current practice, however, reflects the available evidence about patients preferences. Most women consider the reduction in the risk of recurrence as the single most important factor for selecting local therapy for breast cancer (18). A study comparing quality of life after breast cancer reported comparable perceptions of the risk of recurrence and dying of breast cancer among DCIS and invasive breast cancer carriers (19). Fig. 1. Example of a patient treated to the right breast with good cosmetic result. Fig. 2. Example of a patient treated to the right breast with a poor cosmetic result: retraction and hyperpigmentation are detectable at 30-month follow-up. Most DCIS patients, despite being informed of the lack of an effect on breast cancer mortality, tend to choose to undergo adjuvant radiotherapy, expressing their deep concern about the risk of any recurrence. At the same time, the results of a recent survey demonstrates a gap between patients most common preferences for radiotherapy and what radiation oncologists tend to offer (20). In this study, most women favored a shorter course of radiotherapy over the standard 5-6 weeks offered at most radiation centers. It seems reasonable that, particularly in a clinical setting where radiotherapy is unlikely to have an effect on breast cancer survival, more accelerated regimens and consequently, more convenience to the patient, should be actively explored. Multiple prospective studies have evaluated accelerated hypofractionation in patients with invasive disease and have been established as effective treatment regimens for early invasive breast cancer (8, 9). Much less evidence on this subject, however, exists for DCIS. Similarly, the need for a boost remains unsettled: prospective randomized trials testing the role of radiotherapy in DCIS consistently used a dose of 50 Gy in 25 fractions without the inclusion of a boost to the tumor bed. Several ongoing studies address the issue of optimal fractionation and suitability of a boost in DCIS patients. The Trans Tasman Radiation Oncology Group, in association with the Breast International Group, National Cancer Institute of Canada Clinical Trials Group, and the European Organization for Research and Treatment of Cancer recently initiated an international, multi-institutional 4-arm randomized study. DCIS patients are randomly assigned to whole-breast radiotherapy: 50 Gy in 25 fractions or 42.5 Gy in 16 fractions, with or without a tumor bed boost (12). A similar trial is ongoing in France: all patients receive 50 Gy to the breast and are then randomly assigned to a boost of 16 Gy vs no boost (11). Results from these trials will not be available for several years. In our study, 93/145 (63%) of the patients were estrogenpositive and 68% of them (63/93) received either tamoxifen or aromatase inhibitors. Interestingly, half of the recurring patients (3/6) in this series recurred at the tumor bed, in 2/3 cases despite the fact that they had received a daily concomitant boost (as part of the second

6 e164 Ciervide et al. International Journal of Radiation Oncology Biology Physics trial). In each of these cases, the patient carried ER þ tumor, and had either interrupted or refused to undergo the recommended antihormonal therapy. Of note, 3/6 women who recurred did not adhere to the prescription of a full course of tamoxifen. Whether a better compliance with antihormonal therapy would have prevented the recurrence cannot be excluded. In conclusion, these preliminary results suggest that DCIS patients can be safely treated with a shorter regimen of radiotherapy. So far all recurrences were of noninvasive histology. Of notice, Radiation Therapy Oncology Group 1005, a Phase III trial of accelerated whole breast irradiation with hypofractionation plus concurrent boost vs standard whole breast irradiation plus sequential boost, include access to pathological Stage 0 (TIS,N0,M0) breast cancer patients with nuclear grade 3 DCIS and age <50 years. In this study the dose and fractionation regimen in the experimental arm is almost identical (a daily dose of 2.67 Gy þ 0.53 Gy boost, versus NYU dose of 2.7 Gy þ 0.50 Gy boost, in both cases for 15 fractions total) to the ones used for the 86 patients in this series that were treated as part of NYU The prospective randomized trial will generate evidence with regards to the role of this approach in DCIS. References 1. Virnig BA, Tuttle TM, Shamliyan T, et al. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst 2010;102:170e Fisher B, Dignam J, Wolmark N, et al. Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 1998;16:441e Houghton J, George WD, Cuzick J, et al. 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