Salvage radiotherapy for second oligo-recurrence in patients with breast cancer

Salvage radiotherapy for second oligo-recurrence in patients with breast cancer Journal of Radiation Research, Vol. 59, No. 1, 2018, pp. 58–66 doi: 10.1093/jrr/rrx066 Advance Access Publication: 22 November 2017 Salvage radiotherapy for second oligo-recurrence in patients with breast cancer 1 1, 1 2 Mari Miyata , Takayuki Ohguri , Katsuya Yahara , Shinsaku Yamaguchi , 3 1 Hajime Imada and Yukunori Korogi Department of Radiology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan Department of Radiology, Kitakyushu General Hospital, 1-1 Higashijonomachi Kokurakita-ku, Kitakyushu 802-8517, Japan Department of Cancer Therapy Center, Tobata Kyoritsu Hospital, 2-5-1 Sawami Tobata-ku, Kitakyushu 804-0093, Japan *Corresponding author. Department of Radiology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. Tel: +81-93-691-7264; Fax: +81-93-692-0249; Email: ogurieye@med.uoeh-u.ac.jp (Received 22 February 2017; revised 9 June 2017; editorial decision 11 October 2017) ABSTRACT A new concept designated ‘oligo-recurrence (OR)’ has been proposed, which indicates one to several distant metastases/recurrences in one or more organs, which can be treated with local therapy, after the primary site of the cancer has been controlled. The purpose of this study was to assess the efficacy and toxicity of salvage radio- therapy (RT) for the second OR of breast cancer. The second OR was defined as once-salvaged patients with OR who had a second failure that was also detected as the state of OR. Twenty-one patients with second OR were treated with salvage RT and were retrospectively analyzed. The sites of the second OR were locoregional recurrence in 7 patients and distant metastasis in 14 patients. Salvage RT was performed at a median total dose of 60 Gy. Nineteen (90%) patients had an objective response. The median overall survival and progression-free survival (PFS) times were 41 and 24 months after salvage RT for the second OR, respectively. The 3-year local (in-field) control (LC) rates were 93%. The toxicities were mild; acute toxicities ≥Grade 3 were seen in one patient with Grade 3 dermatitis, and no late toxicity ≥Grade 2 was observed. In conclusion, salvage RT for the second OR was able to achieve a better LC rate and longer PFS time without inducing severe toxicity, and there- fore may be a potentially effective modality for inducing long-term survival in select patients. Keywords: breast cancer; recurrence; radiotherapy; oligometastases; oligo-recurrence INTRODUCTION with a longer disease-free interval have an excellent prognosis after Despite significant advances in the primary treatment for breast can- complete resection [8–10]. Recently, curative-intent RT to salvage cer patients, locoregional recurrence (LRR) occurs in 3–20% of the isolated pulmonary metastasis also demonstrated favorable clin- patients treated with breast-conserving therapy, and in 2–12% of ical outcomes [11]. These findings confirm that a subset of breast patients receiving mastectomy in large clinical trials [1]. However, cancer patients with isolated LRR or distant metastasis can be several studies have demonstrated that some patients with an iso- salvaged. lated LRR have long-term survival after salvage local treatment Hellmann et al. defined the term ‘oligometastases’ as a limited [2–7]. Chagpar et al. reported the clinical outcomes in 130 patients metastasis with a maximum of 3 to 4 clinically detectable metastases with an isolated LRR; time to recurrence of >24 months and node- [12]. Patients with oligometastases have a better prognosis, and negative status at presentation were strong predictors of a longer curative local therapy (such as radiotherapy, surgical resection and survival prognosis, particularly if the patients were treated with radiofrequency ablation) plays an important role in further develop- radiotherapy (RT) [7]. On the other hand, several studies have ment of the disease. Recently, Niibe et al. proposed a new concept indicated that surgical resection for isolated pulmonary metastases referred to as ‘oligo-recurrence (OR)’ to eliminate the uncontrolled after mastectomy or breast-conserving therapy may result in long- primary site with several distant metastases from the oligometas- term survival for a substantial number of patients, and that patients tases, and defined the conditions of OR as follows: (i) one to © The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re- use, please contact journals.permissions@oup.com � 58 Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Radiotherapy for second oligo-recurrence � 59 several distant metastases/recurrences in one to several organs; (ii) primary site of the cancer controlled; (iii) one to several distant metastases/recurrences that can be treated with local therapy; and (iv) no distant metastases/recurrences other than those in (iii) [13]. Therefore, the state of OR indicates that all gross metastatic or recurrent sites could be treated with local therapy. A previous study demonstrated that first failure was detected as the state of OR, such as isolated LRR and pulmonary metastasis after mastec- tomy or breast-conserving therapy, and could be salvage by local therapy; however, a subset of once-salvaged patients with OR could have a second failure that was also detected as the state of OR. We have often experienced this situation in patients with breast cancer and have defined it as ‘second OR.’ In many cases, definitive RT has been selected to salvage the second OR at our institutions. However, to the best of our knowledge, there have been no reports of salvage RT for the second OR. The purpose of this study was to assess the efficacy and toxicity of salvage RT for the second OR of breast cancer and to identify the predictors of survival. MATERIALS AND METHODS Patients Fig. 1. Diagram showing the therapeutic process in From December 2000 to October 2013, patients with recurrent or patients who were included in this retrospective metastatic breast cancer were prospectively recorded in the database study. RT = radiotherapy, NED = no evidence of for RT at the authors’ institutions. During the same period, 487 disease, OR = oligo-recurrence. consecutive patients with recurrent or metastatic breast cancer were treated with RT. There were 21 consecutive breast cancer patients with second OR who were treated with salvage RT. All of the 21 trastuzumab in 2 patients, and tegafur-uracil in 1 patient. Nine patients satisfied the following requirements of our definition for second OR and were included in this retrospective study: (i) patients were treated with hormonal therapy after the initial surgery. patients had a pathologically confirmed breast carcinoma; (ii) Only one patient was treated with neoadjuvant chemotherapy, including FEC and docetaxel, before the initial surgery. disease-free status after initial therapy for clinically localized breast The period between the initial surgery and first OR ranged from cancer had been confirmed once based on the results of a physical examination, postoperative pathological findings and computed 4 to 108 months (median, 35 months). The numbers of sites of the first OR were as follows: one site in 20 patients (locoregional recur- tomography (CT); (iii) first failure was detected as OR (first OR), and disease control of the first OR after salvage local therapy was rence in 14 patients and distant metastasis in 6 patients) and two confirmed, while simultaneously there were no other distant metas- sites in 1 patient (Table 1). The local therapies for the first OR were as follows: RT alone in 10 patients, surgery alone in 5 patients, tases/recurrences, based on the results of a physical examination and surgery plus postoperative RT in 6 patients. Five patients and longitudinal CT; (iv) second failure was also detected as OR (second OR), and was treated with salvage RT when the primary received systemic chemotherapy for the first OR followed by local therapies as follows: capecitabine in 3 patients, and EC (cyclophos- site and the first OR were under control before the diagnosis of the second OR (Fig. 1). Written informed consent for treatment was phamide and epirubicin) in 2 patients. Four patients were treated obtained from all patients. The study was approved by the authors’ with concomitant systemic therapy during the course of RT as fol- Institutional Review Boards. lows: docetaxel in 2 patients, paclitaxel in one patient, and tegafur- uracil in one patient. Seven patients received adjuvant chemotherapy The patient characteristics for the second OR are listed in Table 1. For the initial therapy, mastectomy was performed in 13 after local therapy for the first OR using tegafur–uracil in 2 patients, trastuzumab in one patient, trastuzumab in combination with eribulin patients and breast-conserving surgery in 8. The tumor/node/ metastasis (TNM) stages (based on the International Union in one patient, docetaxel in one patient, eribulin in one patient, and Against Cancer TNM classification, 6th edition) were pathologically cisplatin in one patient. Hormonal therapy for the first OR was also evaluated at the initial surgery: Stage I in one patient, Stage IIA in used in 9 patients. The time between the initial surgery and salvage RT for the eight patients, Stage IIB in eight patients, Stage IIIA in two patients, second OR ranged from 22 to 197 months (median, 61 months). and Stage IIIB in two patients. After the initial surgery, 7 patients The time between the local therapy for the first OR and salvage RT were treated with postoperative RT, and 7 patients received adju- vant chemotherapy after the initial surgery as follows: FEC (cyclo- for the second OR ranged from 6 to 89 months (median, 25 months). Table 1 shows the patient characteristics. The Eastern phosphamide, epirubicin, 5-fluorouracil) in 2 patients, CAF (cyclophosphamide, adriamycin, 5-fluorouracil) in 2 patients, Cooperative Oncology Group performance status was evaluated at Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 60 � M. Miyata et al. Table 1. Patient characteristics Table 1. Continued Variable n = 21 (%) Variable n = 21 (%) Median age (range) 66 (47–82) Multiple lung metastases 1 Initial surgery for primary breast cancer Supraclavicular (contralateral), cervical and 1 parasternal LN Total resection 13 (62) OR = oligo-recurrence, LN = lymph node, RT = radiotherapy, LRR = loco- Partial resction 8 (38) regional recurrence. Site(s) of the first OR One site 20 (95) the start of the salvage RT for the second OR. The subtype status was based on the original region. Two of the 21 patients were LRR pathologically diagnosed as having second OR, and the remaining Supraclavicular LN 6 19 patients were diagnosed based on longitudinal computed tomog- raphy (CT) scans and tumor marker levels; in some cases, magnetic Chest wall 6 resonance imaging (n = 3) and/or F-fluorodeoxyglucose positron Axillary LN 2 emission tomography/CT (n = 2) were also used. The sites of the second OR are listed in Table 1. Distant metastasis The treatment methods for the second OR are shown in Table 2. Two of the 21 patients received systemic chemotherapy for Bone 4 the second OR followed by salvage RT as follows: tegafur–uracil in Lung 2 one patient, and trastuzumab in one patient. Six patients were trea- ted with concomitant systemic chemotherapy during the course of Two sites 1 (5) RT as follows: vinorelbine in 2 patients, docetaxel in 2 patients, Supraclavicular and parasternal LN 1 paclitaxel in one patient, and tegafur-uracil in one patient. Four patients received adjuvant chemotherapy after the salvage RT for Local therapy for the first OR the second OR using capecitabine in one patient, tegafur–uracil in RT alone 10 (48) one patient, docetaxel in one patient, and paclitaxel in one patient. Hormonal therapy for the second OR was also used in 9 patients. Surgery alone 5 (24) Surgery+postoperative RT 6 (29) Salvage RT for the second OR Site(s) of the second OR All the 21 patients were treated with external RT (Table 2). The total radiation dose of the salvage RT, using a 4, 6 or 10 MV linear One site 17 (81) accelerator, ranged from 40 to 76 Gy (median, 60 Gy), the daily dose was 2.0–3.0 Gy (median, 2.0 Gy), and, exceptionally, one LRR patient with brain metastasis was treated with whole-brain RT Axillary LN 4 (30 Gy in 10 fractions) plus stereotactic RT (35.2 Gy in 8 frac- tions). Computed tomography–assisted three-dimensional treatment Supraclavicular LN 3 planning (Xio or FOCUS; CMS Japan, Tokyo, Japan) was used to Distant metastasis determine the radiation fields in all of the 21 patients. Prophylactic nodal irradiation for axillary or supraclavicular lymph node (LN) Bone 5 lesions was administered in 4 patients; the clinical target volume Mediastinal LN 3 (CTV) was defined as the gross tumor volume (GTV) and the axil- lary LN area plus a 0.5 cm margin. Prophylactic irradiation was also Brain 1 performed for the mediastinal LN region in 2 patients and whole Lung 1 brain in one patient. The planning target volume (PTV) included the CTV plus a 1.0–2.0 cm margin for the daily set-up variation. Two sites 2 (10) Normally, the initial field area covered the PTV with a two-field or four-field box technique, and the field was then shrunk to the GTV Parasternal LN and pleura 1 (tumor of the second OR) with 0.5–1.5 cm margins at a dose of Thoracic spine and iliac bone 1 40–50 Gy for the boost doses of 10–20 Gy using a multifield beam arrangement or conformational therapy. The remaining patients Three sites 2 (10) were treated without prophylactic irradiation and with RT using a Continued three-dimensional conformal technique; the CTV was defined as Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Radiotherapy for second oligo-recurrence � 61 Table 2. Treatment methods for the second oligo-recurrence Variable n = 21 (%) Salvage RT for the second OR Median total dose (Gy, range) 60 (40–76) Median daily dose (Gy, range) 2 (2–3) Tumor response to neoadjuvant systemic therapy 11 (52) before salvage RT for the second OR Hormonal therapy NC 4 PD 5 Chemotherapy NC 1 Fig. 2. Overall survival (OS), progression-free survival (PFS), and local (in-field) control rates (LC) after salvage PD 1 radiotherapy (RT) for the second oligo-recurrence (OR). Concurrent systemic therapy during the salvage RT 15 (71) for the second OR Progressive disease (PD) was defined as either a 25% increase in measurable lesions or the appearance of any new measurable or non- Hormonal therapy 9 measurable lesions. Patients who did not meet the definitions of response or progression were classified as having no change (NC). Chemotherapy 6 The overall survival (OS), progression-free survival (PFS) and Adjuvant systemic therapy after the salvage RT for the 10 (48) local control (LC) (defined as failure to have a recurrence within second OR the radiation field for the second OR) rates were calculated from the start of the salvage RT for the second OR using the Kaplan– Hormonal therapy 6 Meier method. The statistical significance of the difference between Chemotherapy 4 the actuarial curves was assessed using the log-rank test. To identify the prognostic factors for the OS and PFS rates, univariate analyses OR = oligo-recurrence, RT = radiotherapy, NC = no change, PD = progressive were performed. A multivariate analysis was not performed due to disease. the small number of patients. The National Cancer Institute Common Toxicity Criteria ver- the GTV plus 0.5 cm, and the PTV was the CTV plus 0.5–1.5 cm sion 3 (CTCAE) was used to score the patient toxicity. The highest for the daily set-up variation and respiratory movement. toxicity grade obtained for each patient was used for the toxicity Four (19%) of the 21 patients were also treated with hyperthermia analysis. The toxicity was defined as acute (during therapy and up during the salvage RT. Hyperthermia was applied after irradiation to 3 months after the combination therapy) or late (over 3 months once per week for radiosensitization via the 8-MHz radiofrequency- after the completion of the combination therapy). capacitive regional hyperthermia system (Thermotron RF-8; Yamamoto Vinita, Osaka, Japan) [14, 15]. The heating duration was RESULTS adjusted from 40 to 50 min based on the patient’s tolerance (median, The median follow-up for the surviving patients after the salvage 50 min). The number of hyperthermia treatments during the RT ran- RT for the second OR was 25 months (range, 3–156 months). All ged from 2 to 5 (median, 5). patients completed the planned radiation treatments. Nineteen (90%) of the 21 patients experienced an objective response; CR in Evaluation and follow-up 12 patients, PR in 7 patients, and NC in 2 patients. The first sites of The objective tumor response was evaluated by measuring the disease progression after the salvage RT for the second OR were tumor size by CT before and 1–6 months after salvage RT for the out-field alone in 11 patients (52%) (axillary LN in 3 patients, lung second OR, and follow-up evaluations were performed by CT every in 2 patients, supraclavicular LN in one patient, brain in one patient, 1–6 months. The treatment response was evaluated according to bone in one patient, and multiple organs in 3 patients) and both in- the World Health Organization criteria [16]. A complete response field and out-field in 2 patients (10%); none of the patients had first (CR) was defined as the complete disappearance of all clinically sites locally (in-field) alone. All of the patients with disease progres- detectable tumors for at least 4 weeks. A partial response (PR) was sion after salvage RT for second OR underwent various types of sys- defined as a minimum 50% reduction in the sum of the products of temic therapy and/or local treatment. Three patients were treated the longest perpendicular diameters of all measurable lesions. with third salvage RT after second OR, and one patient underwent Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 62 � M. Miyata et al. Table 3. The results of the univariate analyses of factors predicting the survival rates after the salvage RT for the second oligo- recurrence Variable n Overall survival rate Progression-free survival rate 2-year (%) P 2-year (%) P Age 0.0808 0.199 <60 year 6 83 67 ≥60 year 15 83 45 Hormonal status 0.964 0.452 Positive 9 86 49 Negative 12 80 50 Subtype 0.636 0.877 Triple negative 5 80 40 Others 16 84 54 Site of the second OR 0.0405 0.347 Soft tissue 13 90 52 Visceral organ or bone 8 71 47 Tumor size of the second OR 0.267 0.824 ≥3 cm 8 71 38 <3cm 13 91 60 Pattern of the first and second OR NR 0.922 LRR→LRR 7 100 54 LRR→DM or DM→DM 14 77 49 Total dose of salvage RT for the second OR 0.0561 0.173 ≥51 Gy 12 91 56 <51 Gy 9 71 42 Objective tumor response 0.129 0.437 CR 12 90 47 non-CR 9 75 53 Adjuvant systemic therapy after salvage RT for the second OR 0.777 0.659 Yes 9 88 56 No 12 79 48 Period between start of initial surgery and the second OR 0.768 0.951 ≥72 months 8 86 50 <72 months 13 82 52 RT = radiotherapy, OR = oligo-recurrence, CR = complete response, NR = not reached, LRR = loco-regional recurrence, DM = distant metastasis. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Radiotherapy for second oligo-recurrence � 63 Fig. 3. Presence of the recurrence within soft tissue, compared to that within a visceral organ or bone, was Fig. 5. Patients associated with the first oligo-recurrences significantly associated with a better overall survival (OS) (ORs) of loco-regional recurrence (LRR) and the second ORs rate after salvage radiotherapy (RT) for the second oligo- of LRR did not achieve better progression-free survival (PFS) recurrence (OR). rate after salvage radiotherapy (RT) for the second OR. and 24 months, respectively. The univariate analyses indicated that location of the second OR in soft tissue was significant for achieving a better OS rate (Table 3, Fig. 3). The total dose of salvage RT for the second OR (≥51 Gy) and age (<60 years) tended to be signifi- cant factors for achieving a better OS rate (Fig. 4). Patients asso- ciated with the first OR of the LRR and second OR of the LRR did not show a better PFS rates (Table 3, Fig. 5). DISCUSSION The present study is, to the best of our knowledge, the first study to evaluate the efficacy and toxicity of salvage RT for a second OR as a selected type of metastatic/recurrent breast cancer. As most cases of metastatic/recurrent breast cancer are not curable, the standard management of these patients has been systemic chemo- therapy; however, as aforementioned, local therapy may play an important role in treating patients with OR. The previously Fig. 4. The total dose of the salvage radiotherapy (RT)_ for reported therapeutic results for salvage local therapy for the condi- the second oligo-recurrence (OR) (≥51 Gy) tended to tion of OR can be divided into two categories. One is isolated LRR achieve a significantly better overall survival (OS) rate after after disease-free status has been achieved by initial therapy for breast salvage RT for the second OR (P = 0.0561). cancer. The other is isolated distant metastasis after the disease-free status (Table 4)[2–6, 8–10, 17–21]. In most of those results, the lesions of OR conformed to the first OR. However, a subset of once- fourth salvage RT. During the follow-up period, 8 (38%) of the 21 salvaged patients with the first OR may have had second OR. patients were alive without disease, and 6 patients (29%) were alive Selecting this subset of patients for study means that, our selection of with disease. Seven patients (33%) died after second OR. patients for salvage RT is unique. The observed toxicities were mild. Acute toxicities ≥Grade 2 For previously reported clinical outcomes of the isolated LRR as occurred in 10 patients (48%): Grade 3 dermatitis in one patient, the first OR, Table 4 indicates that the 5-year OS ranged from 34% Grade 2 dermatitis in 7 patients, and Grade 2 esophagitis in 2 to 62% after local salvage therapy. Jeong et al. demonstrated the patients. No late toxicities ≥Grade 2 were observed. clinical outcomes for surgery plus postoperative RT or RT alone in The 2-year OS, PFS, and LC (in-field) rates after RT for the 71 cases of breast cancer patients with isolated LRR after mastec- second OR were 83%, 51% and 93%, respectively (Fig. 2). The 3- tomy. Second isolated LRR occurred in 5 (7%) patients, 3 of whom year OS, PFS, and LC (in-field) rates were 65%, 26% and 93%, received surgery and 1 of whom received RT; single-site metastasis respectively. The median survival times (MST) with regard to the occurred in 26 (37%) patients [6]. Those patients were comparable OS and PFS rates after the salvage RT for the second OR were 41 with the patients who experienced second OR. However, the Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 64 � M. Miyata et al. Table 4. Major reports of the local therapy for the oligo-recurrence and the results of the current study in patients with breast cancer Series (Ref.) Year No. of No. of patients Site of Local therapy Treatment outcomes patients with the first OR (%) the OR Isolated LRR Magno [2] 1987 162 162 (100) LRR surgery+RT or RT 5-year OS; 34%, 5-year DFS; 28% Schwaibold [3] 1991 128 128 (100) LRR surgery+RT or RT 5-year OS; 49%, 5-year DFS; 24%, 5-year LRC; 43%, Deutsch [4] 2000 70 70 (100) LRR RT 5-year OS; 36%, CR rate; 87%. Kuo [5] 2008 115 115 (100) LRR surgery+RT or RT 5-year OS; 57%, MST; 106 months, MDFS; 52 months Jeong [6] 2013 71 71 (100) LRR surgery+RT or RT 5-year OS; 62%, MST; 87 months, MDFS; 36 months Isolated DM McDonald [8] 1994 60 60 (100) lung surgery 5-year OS; 38%, MST; 42 months, MDFS; 18 months Planchard [9] 2004 125 125 (100) lung surgery 5-year OS; 45% , MST; 50 months Welter [10] 2008 47 40 (85) lung surgery 5-year OS; 36%, MST; 32 months Milano [11] 2009 40 36 (90) lung SBRT 4-year OS; 59%, 4-year PFS; 38%, 4-year LC; 89% Raab [18] 1998 34 29 (85) liver surgery 5-year OS; 18%, MST; 27 months Selzner [19] 2000 17 14 (82) liver surgery 5-year OS; 22%, MST; 24 months, 5-year DFS; 17% Kondziolka [20] 2011 24 N.A. brain SRS ± WBRT MST 17 months Niibe [21] 2008 7 N.A. bone RT All the patients were alive at the last follow-up. Present study 21 second OR various RT 5-year OS; 34%, MST; 41 months, MPFS; 24 months OR = oligo-recurrence, LRR = loco-regional recurrence, DM = distant metastasis, SBRT = stereotactic body radiotherapy, SRS = stereotactic radiosurgery, WBRT = whole-brain radiotherapy, OS = overall survival, DFS = disease-free survival, LRC = local and/or regional control, CR = complete response, MST = median survival time, MDFS = median disease-free survival, PFS = progression-free survival, MPFS = median progression-free survival, N.A. = not available. Twenty-seven patients were treated with systemic therapy alone. treatment outcomes for the second OR were not described. Kuo OR, the 5-year OS rates after salvage local therapy ranged from et al. also reported that the 5-year OS rate was 57% in 115 patients 18% to 45% (Table 4). McDonald et al. reported the clinical out- with isolated LRR treated with local therapy; 20 (17%) had a comes in 60 patients with pulmonary metastasis treated with surgery second isolated LRR after local therapy, which was comparable with as the first OR, and observed that pulmonary metastases of the a second OR. However, treatment details for the second OR were second OR treated with a second thoracotomy occurred in not stated [5]. In the present study, 7 patients had isolated LRR as 2 patients. One patient had a wedge excision 9 months after the ini- the second OR; they were treated with salvage RT and showed tial pulmonary resection, but expired due to disease recurrence 33 favorable treatment outcomes without severe toxicity; the 2-year months after the second thoracotomy. The other patient had a lob- OS, LC and PFS after salvage RT for the second OR were 100%, ectomy 6.3 years after the initial thoracotomy and is still living 24 100% and 54%, respectively. months later without evidence of disease [8]. Distant metastasis in patients with breast cancer tends to occur Recently, several studies have shown that curative-intent RT in the lung, bone, liver, brain, and lymph nodes [22]. In previously using modern techniques in patients with oligometastatic disease, reported treatment results of those distant metastases as the first including breast cancer, have resulted in good local tumor control Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Radiotherapy for second oligo-recurrence � 65 without severe toxicity [23]. Milano et al. reported that a prospect- inducing severe toxicity and is a promising treatment that may result ive study of curative-intent stereotactic RT in patients with 5 or few- in long-term survival in select patients with second OR. Further eva- er oligometastatic lesions at various sites demonstrated that breast luations with detailed treatment protocols are necessary in order to cancer patients had significant improvements in their OS rates; the clarify whether salvage RT could improve survival in breast patients 4-year OS rates in the breast cancer and non-breast cancer patients with second OR. were 54% and 16%, respectively [17]. The same study also reported the clinical outcomes of curative-intent stereotactic RT in 40 CONFLICTOF INTEREST patients with oligometastatic breast cancer; 36 (90%) patients were There are no conflicts of interest. comparable with patients experiencing a first OR; they achieved a 4-year OS of 59% [11]. 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Capacitive heating of phan- irradiation of the LN area achieved high locoregional control rates tom and human tumors with an 8 MHz radiofrequency applica- without severe toxicity in breast cancer patients with OR in the LNs tor (Thermotron RF-8). Int J Radiat Oncol Biol Phys 1986;12: [6, 29, 30]. A formal prospective trial with detailed treatment proto- 365–72. cols is needed in order to determine the efficacy of and prognostic 15. Abe M, Hiraoka M, Takahashi M et al. Multi-institutional stud- factors for this therapy in breast cancer patients with second OR. ies on hyperthermia using an 8-MHz radiofrequency capacitive In conclusion, salvage RT in breast cancer patients with second heating device (Thermotron RF-8) in combination with radi- OR may achieve a long-term PFS time and high LC rate without ation for cancer therapy. Cancer 1986;58:1589–95. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 66 � M. 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Tomiak E, Piccart M, Mignolet F et al. Characterisation of com- from breast cancer: long-term survival after curative resection. plete responders to combination chemotherapy for advanced Surgery 2000;127:383–9. breast cancer: a retrospective EORTC Breast Group study. Eur 20. Kondziolka D, Kano H, Harrison GL et al. Stereotactic radio- J Cancer 1996;32A:1876–87. surgery as primary and salvage treatment for brain metastases 28. Rashaan ZM, Bastiaannet E, Portielje JE et al. Surgery in metastatic from breast cancer. Clinical article. J Neurosurg 2011;114: breast cancer: patients with a favorable profile seem to have the 792–800. most benefitfromsurgery. Eur J Surg Oncol 2012;38:52–6. 21. Niibe Y, Kuranami M, Matsunaga K et al. Value of high-dose 29. Reddy JP, Levy L, Oh JL et al. Long-term outcomes in patients radiation therapy for isolated osseous metastasis in breast cancer with isolated supraclavicular nodal recurrence after mastectomy in terms of oligo-recurrence. Anticancer Res 2008;28:3929–31. and doxorubicin-based chemotherapy for breast cancer. Int J 22. Singletary SE, Walsh G, Vauthey JN et al. A role for curative Radiat Oncol Biol Phys 2011;80:1453–7. surgery in the treatment of selected patients with metastatic 30. Pergolizzi S, Adamo V, Russi E et al. Prospective multicenter breast cancer. Oncologist 2003;8:241–51. study of combined treatment with chemotherapy and radiother- 23. Niibe Y, Chang JY. Novel insights of oligometastases and oligo- apy in breast cancer women with the rare clinical scenario recurrence and review of the literature. Pulm Med 2012;2012: of ipsilateral supraclavicular node recurrence without distant 261096. metastases. Int J Radiat Oncol Biol Phys 2006;65:25–32. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Radiation Research Oxford University Press

Salvage radiotherapy for second oligo-recurrence in patients with breast cancer

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Journal of Radiation Research, Vol. 59, No. 1, 2018, pp. 58–66 doi: 10.1093/jrr/rrx066 Advance Access Publication: 22 November 2017 Salvage radiotherapy for second oligo-recurrence in patients with breast cancer 1 1, 1 2 Mari Miyata , Takayuki Ohguri , Katsuya Yahara , Shinsaku Yamaguchi , 3 1 Hajime Imada and Yukunori Korogi Department of Radiology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan Department of Radiology, Kitakyushu General Hospital, 1-1 Higashijonomachi Kokurakita-ku, Kitakyushu 802-8517, Japan Department of Cancer Therapy Center, Tobata Kyoritsu Hospital, 2-5-1 Sawami Tobata-ku, Kitakyushu 804-0093, Japan *Corresponding author. Department of Radiology, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. Tel: +81-93-691-7264; Fax: +81-93-692-0249; Email: ogurieye@med.uoeh-u.ac.jp (Received 22 February 2017; revised 9 June 2017; editorial decision 11 October 2017) ABSTRACT A new concept designated ‘oligo-recurrence (OR)’ has been proposed, which indicates one to several distant metastases/recurrences in one or more organs, which can be treated with local therapy, after the primary site of the cancer has been controlled. The purpose of this study was to assess the efficacy and toxicity of salvage radio- therapy (RT) for the second OR of breast cancer. The second OR was defined as once-salvaged patients with OR who had a second failure that was also detected as the state of OR. Twenty-one patients with second OR were treated with salvage RT and were retrospectively analyzed. The sites of the second OR were locoregional recurrence in 7 patients and distant metastasis in 14 patients. Salvage RT was performed at a median total dose of 60 Gy. Nineteen (90%) patients had an objective response. The median overall survival and progression-free survival (PFS) times were 41 and 24 months after salvage RT for the second OR, respectively. The 3-year local (in-field) control (LC) rates were 93%. The toxicities were mild; acute toxicities ≥Grade 3 were seen in one patient with Grade 3 dermatitis, and no late toxicity ≥Grade 2 was observed. In conclusion, salvage RT for the second OR was able to achieve a better LC rate and longer PFS time without inducing severe toxicity, and there- fore may be a potentially effective modality for inducing long-term survival in select patients. Keywords: breast cancer; recurrence; radiotherapy; oligometastases; oligo-recurrence INTRODUCTION with a longer disease-free interval have an excellent prognosis after Despite significant advances in the primary treatment for breast can- complete resection [8–10]. Recently, curative-intent RT to salvage cer patients, locoregional recurrence (LRR) occurs in 3–20% of the isolated pulmonary metastasis also demonstrated favorable clin- patients treated with breast-conserving therapy, and in 2–12% of ical outcomes [11]. These findings confirm that a subset of breast patients receiving mastectomy in large clinical trials [1]. However, cancer patients with isolated LRR or distant metastasis can be several studies have demonstrated that some patients with an iso- salvaged. lated LRR have long-term survival after salvage local treatment Hellmann et al. defined the term ‘oligometastases’ as a limited [2–7]. Chagpar et al. reported the clinical outcomes in 130 patients metastasis with a maximum of 3 to 4 clinically detectable metastases with an isolated LRR; time to recurrence of >24 months and node- [12]. Patients with oligometastases have a better prognosis, and negative status at presentation were strong predictors of a longer curative local therapy (such as radiotherapy, surgical resection and survival prognosis, particularly if the patients were treated with radiofrequency ablation) plays an important role in further develop- radiotherapy (RT) [7]. On the other hand, several studies have ment of the disease. Recently, Niibe et al. proposed a new concept indicated that surgical resection for isolated pulmonary metastases referred to as ‘oligo-recurrence (OR)’ to eliminate the uncontrolled after mastectomy or breast-conserving therapy may result in long- primary site with several distant metastases from the oligometas- term survival for a substantial number of patients, and that patients tases, and defined the conditions of OR as follows: (i) one to © The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re- use, please contact journals.permissions@oup.com � 58 Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Radiotherapy for second oligo-recurrence � 59 several distant metastases/recurrences in one to several organs; (ii) primary site of the cancer controlled; (iii) one to several distant metastases/recurrences that can be treated with local therapy; and (iv) no distant metastases/recurrences other than those in (iii) [13]. Therefore, the state of OR indicates that all gross metastatic or recurrent sites could be treated with local therapy. A previous study demonstrated that first failure was detected as the state of OR, such as isolated LRR and pulmonary metastasis after mastec- tomy or breast-conserving therapy, and could be salvage by local therapy; however, a subset of once-salvaged patients with OR could have a second failure that was also detected as the state of OR. We have often experienced this situation in patients with breast cancer and have defined it as ‘second OR.’ In many cases, definitive RT has been selected to salvage the second OR at our institutions. However, to the best of our knowledge, there have been no reports of salvage RT for the second OR. The purpose of this study was to assess the efficacy and toxicity of salvage RT for the second OR of breast cancer and to identify the predictors of survival. MATERIALS AND METHODS Patients Fig. 1. Diagram showing the therapeutic process in From December 2000 to October 2013, patients with recurrent or patients who were included in this retrospective metastatic breast cancer were prospectively recorded in the database study. RT = radiotherapy, NED = no evidence of for RT at the authors’ institutions. During the same period, 487 disease, OR = oligo-recurrence. consecutive patients with recurrent or metastatic breast cancer were treated with RT. There were 21 consecutive breast cancer patients with second OR who were treated with salvage RT. All of the 21 trastuzumab in 2 patients, and tegafur-uracil in 1 patient. Nine patients satisfied the following requirements of our definition for second OR and were included in this retrospective study: (i) patients were treated with hormonal therapy after the initial surgery. patients had a pathologically confirmed breast carcinoma; (ii) Only one patient was treated with neoadjuvant chemotherapy, including FEC and docetaxel, before the initial surgery. disease-free status after initial therapy for clinically localized breast The period between the initial surgery and first OR ranged from cancer had been confirmed once based on the results of a physical examination, postoperative pathological findings and computed 4 to 108 months (median, 35 months). The numbers of sites of the first OR were as follows: one site in 20 patients (locoregional recur- tomography (CT); (iii) first failure was detected as OR (first OR), and disease control of the first OR after salvage local therapy was rence in 14 patients and distant metastasis in 6 patients) and two confirmed, while simultaneously there were no other distant metas- sites in 1 patient (Table 1). The local therapies for the first OR were as follows: RT alone in 10 patients, surgery alone in 5 patients, tases/recurrences, based on the results of a physical examination and surgery plus postoperative RT in 6 patients. Five patients and longitudinal CT; (iv) second failure was also detected as OR (second OR), and was treated with salvage RT when the primary received systemic chemotherapy for the first OR followed by local therapies as follows: capecitabine in 3 patients, and EC (cyclophos- site and the first OR were under control before the diagnosis of the second OR (Fig. 1). Written informed consent for treatment was phamide and epirubicin) in 2 patients. Four patients were treated obtained from all patients. The study was approved by the authors’ with concomitant systemic therapy during the course of RT as fol- Institutional Review Boards. lows: docetaxel in 2 patients, paclitaxel in one patient, and tegafur- uracil in one patient. Seven patients received adjuvant chemotherapy The patient characteristics for the second OR are listed in Table 1. For the initial therapy, mastectomy was performed in 13 after local therapy for the first OR using tegafur–uracil in 2 patients, trastuzumab in one patient, trastuzumab in combination with eribulin patients and breast-conserving surgery in 8. The tumor/node/ metastasis (TNM) stages (based on the International Union in one patient, docetaxel in one patient, eribulin in one patient, and Against Cancer TNM classification, 6th edition) were pathologically cisplatin in one patient. Hormonal therapy for the first OR was also evaluated at the initial surgery: Stage I in one patient, Stage IIA in used in 9 patients. The time between the initial surgery and salvage RT for the eight patients, Stage IIB in eight patients, Stage IIIA in two patients, second OR ranged from 22 to 197 months (median, 61 months). and Stage IIIB in two patients. After the initial surgery, 7 patients The time between the local therapy for the first OR and salvage RT were treated with postoperative RT, and 7 patients received adju- vant chemotherapy after the initial surgery as follows: FEC (cyclo- for the second OR ranged from 6 to 89 months (median, 25 months). Table 1 shows the patient characteristics. The Eastern phosphamide, epirubicin, 5-fluorouracil) in 2 patients, CAF (cyclophosphamide, adriamycin, 5-fluorouracil) in 2 patients, Cooperative Oncology Group performance status was evaluated at Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 60 � M. Miyata et al. Table 1. Patient characteristics Table 1. Continued Variable n = 21 (%) Variable n = 21 (%) Median age (range) 66 (47–82) Multiple lung metastases 1 Initial surgery for primary breast cancer Supraclavicular (contralateral), cervical and 1 parasternal LN Total resection 13 (62) OR = oligo-recurrence, LN = lymph node, RT = radiotherapy, LRR = loco- Partial resction 8 (38) regional recurrence. Site(s) of the first OR One site 20 (95) the start of the salvage RT for the second OR. The subtype status was based on the original region. Two of the 21 patients were LRR pathologically diagnosed as having second OR, and the remaining Supraclavicular LN 6 19 patients were diagnosed based on longitudinal computed tomog- raphy (CT) scans and tumor marker levels; in some cases, magnetic Chest wall 6 resonance imaging (n = 3) and/or F-fluorodeoxyglucose positron Axillary LN 2 emission tomography/CT (n = 2) were also used. The sites of the second OR are listed in Table 1. Distant metastasis The treatment methods for the second OR are shown in Table 2. Two of the 21 patients received systemic chemotherapy for Bone 4 the second OR followed by salvage RT as follows: tegafur–uracil in Lung 2 one patient, and trastuzumab in one patient. Six patients were trea- ted with concomitant systemic chemotherapy during the course of Two sites 1 (5) RT as follows: vinorelbine in 2 patients, docetaxel in 2 patients, Supraclavicular and parasternal LN 1 paclitaxel in one patient, and tegafur-uracil in one patient. Four patients received adjuvant chemotherapy after the salvage RT for Local therapy for the first OR the second OR using capecitabine in one patient, tegafur–uracil in RT alone 10 (48) one patient, docetaxel in one patient, and paclitaxel in one patient. Hormonal therapy for the second OR was also used in 9 patients. Surgery alone 5 (24) Surgery+postoperative RT 6 (29) Salvage RT for the second OR Site(s) of the second OR All the 21 patients were treated with external RT (Table 2). The total radiation dose of the salvage RT, using a 4, 6 or 10 MV linear One site 17 (81) accelerator, ranged from 40 to 76 Gy (median, 60 Gy), the daily dose was 2.0–3.0 Gy (median, 2.0 Gy), and, exceptionally, one LRR patient with brain metastasis was treated with whole-brain RT Axillary LN 4 (30 Gy in 10 fractions) plus stereotactic RT (35.2 Gy in 8 frac- tions). Computed tomography–assisted three-dimensional treatment Supraclavicular LN 3 planning (Xio or FOCUS; CMS Japan, Tokyo, Japan) was used to Distant metastasis determine the radiation fields in all of the 21 patients. Prophylactic nodal irradiation for axillary or supraclavicular lymph node (LN) Bone 5 lesions was administered in 4 patients; the clinical target volume Mediastinal LN 3 (CTV) was defined as the gross tumor volume (GTV) and the axil- lary LN area plus a 0.5 cm margin. Prophylactic irradiation was also Brain 1 performed for the mediastinal LN region in 2 patients and whole Lung 1 brain in one patient. The planning target volume (PTV) included the CTV plus a 1.0–2.0 cm margin for the daily set-up variation. Two sites 2 (10) Normally, the initial field area covered the PTV with a two-field or four-field box technique, and the field was then shrunk to the GTV Parasternal LN and pleura 1 (tumor of the second OR) with 0.5–1.5 cm margins at a dose of Thoracic spine and iliac bone 1 40–50 Gy for the boost doses of 10–20 Gy using a multifield beam arrangement or conformational therapy. The remaining patients Three sites 2 (10) were treated without prophylactic irradiation and with RT using a Continued three-dimensional conformal technique; the CTV was defined as Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Radiotherapy for second oligo-recurrence � 61 Table 2. Treatment methods for the second oligo-recurrence Variable n = 21 (%) Salvage RT for the second OR Median total dose (Gy, range) 60 (40–76) Median daily dose (Gy, range) 2 (2–3) Tumor response to neoadjuvant systemic therapy 11 (52) before salvage RT for the second OR Hormonal therapy NC 4 PD 5 Chemotherapy NC 1 Fig. 2. Overall survival (OS), progression-free survival (PFS), and local (in-field) control rates (LC) after salvage PD 1 radiotherapy (RT) for the second oligo-recurrence (OR). Concurrent systemic therapy during the salvage RT 15 (71) for the second OR Progressive disease (PD) was defined as either a 25% increase in measurable lesions or the appearance of any new measurable or non- Hormonal therapy 9 measurable lesions. Patients who did not meet the definitions of response or progression were classified as having no change (NC). Chemotherapy 6 The overall survival (OS), progression-free survival (PFS) and Adjuvant systemic therapy after the salvage RT for the 10 (48) local control (LC) (defined as failure to have a recurrence within second OR the radiation field for the second OR) rates were calculated from the start of the salvage RT for the second OR using the Kaplan– Hormonal therapy 6 Meier method. The statistical significance of the difference between Chemotherapy 4 the actuarial curves was assessed using the log-rank test. To identify the prognostic factors for the OS and PFS rates, univariate analyses OR = oligo-recurrence, RT = radiotherapy, NC = no change, PD = progressive were performed. A multivariate analysis was not performed due to disease. the small number of patients. The National Cancer Institute Common Toxicity Criteria ver- the GTV plus 0.5 cm, and the PTV was the CTV plus 0.5–1.5 cm sion 3 (CTCAE) was used to score the patient toxicity. The highest for the daily set-up variation and respiratory movement. toxicity grade obtained for each patient was used for the toxicity Four (19%) of the 21 patients were also treated with hyperthermia analysis. The toxicity was defined as acute (during therapy and up during the salvage RT. Hyperthermia was applied after irradiation to 3 months after the combination therapy) or late (over 3 months once per week for radiosensitization via the 8-MHz radiofrequency- after the completion of the combination therapy). capacitive regional hyperthermia system (Thermotron RF-8; Yamamoto Vinita, Osaka, Japan) [14, 15]. The heating duration was RESULTS adjusted from 40 to 50 min based on the patient’s tolerance (median, The median follow-up for the surviving patients after the salvage 50 min). The number of hyperthermia treatments during the RT ran- RT for the second OR was 25 months (range, 3–156 months). All ged from 2 to 5 (median, 5). patients completed the planned radiation treatments. Nineteen (90%) of the 21 patients experienced an objective response; CR in Evaluation and follow-up 12 patients, PR in 7 patients, and NC in 2 patients. The first sites of The objective tumor response was evaluated by measuring the disease progression after the salvage RT for the second OR were tumor size by CT before and 1–6 months after salvage RT for the out-field alone in 11 patients (52%) (axillary LN in 3 patients, lung second OR, and follow-up evaluations were performed by CT every in 2 patients, supraclavicular LN in one patient, brain in one patient, 1–6 months. The treatment response was evaluated according to bone in one patient, and multiple organs in 3 patients) and both in- the World Health Organization criteria [16]. A complete response field and out-field in 2 patients (10%); none of the patients had first (CR) was defined as the complete disappearance of all clinically sites locally (in-field) alone. All of the patients with disease progres- detectable tumors for at least 4 weeks. A partial response (PR) was sion after salvage RT for second OR underwent various types of sys- defined as a minimum 50% reduction in the sum of the products of temic therapy and/or local treatment. Three patients were treated the longest perpendicular diameters of all measurable lesions. with third salvage RT after second OR, and one patient underwent Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 62 � M. Miyata et al. Table 3. The results of the univariate analyses of factors predicting the survival rates after the salvage RT for the second oligo- recurrence Variable n Overall survival rate Progression-free survival rate 2-year (%) P 2-year (%) P Age 0.0808 0.199 <60 year 6 83 67 ≥60 year 15 83 45 Hormonal status 0.964 0.452 Positive 9 86 49 Negative 12 80 50 Subtype 0.636 0.877 Triple negative 5 80 40 Others 16 84 54 Site of the second OR 0.0405 0.347 Soft tissue 13 90 52 Visceral organ or bone 8 71 47 Tumor size of the second OR 0.267 0.824 ≥3 cm 8 71 38 <3cm 13 91 60 Pattern of the first and second OR NR 0.922 LRR→LRR 7 100 54 LRR→DM or DM→DM 14 77 49 Total dose of salvage RT for the second OR 0.0561 0.173 ≥51 Gy 12 91 56 <51 Gy 9 71 42 Objective tumor response 0.129 0.437 CR 12 90 47 non-CR 9 75 53 Adjuvant systemic therapy after salvage RT for the second OR 0.777 0.659 Yes 9 88 56 No 12 79 48 Period between start of initial surgery and the second OR 0.768 0.951 ≥72 months 8 86 50 <72 months 13 82 52 RT = radiotherapy, OR = oligo-recurrence, CR = complete response, NR = not reached, LRR = loco-regional recurrence, DM = distant metastasis. Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Radiotherapy for second oligo-recurrence � 63 Fig. 3. Presence of the recurrence within soft tissue, compared to that within a visceral organ or bone, was Fig. 5. Patients associated with the first oligo-recurrences significantly associated with a better overall survival (OS) (ORs) of loco-regional recurrence (LRR) and the second ORs rate after salvage radiotherapy (RT) for the second oligo- of LRR did not achieve better progression-free survival (PFS) recurrence (OR). rate after salvage radiotherapy (RT) for the second OR. and 24 months, respectively. The univariate analyses indicated that location of the second OR in soft tissue was significant for achieving a better OS rate (Table 3, Fig. 3). The total dose of salvage RT for the second OR (≥51 Gy) and age (<60 years) tended to be signifi- cant factors for achieving a better OS rate (Fig. 4). Patients asso- ciated with the first OR of the LRR and second OR of the LRR did not show a better PFS rates (Table 3, Fig. 5). DISCUSSION The present study is, to the best of our knowledge, the first study to evaluate the efficacy and toxicity of salvage RT for a second OR as a selected type of metastatic/recurrent breast cancer. As most cases of metastatic/recurrent breast cancer are not curable, the standard management of these patients has been systemic chemo- therapy; however, as aforementioned, local therapy may play an important role in treating patients with OR. The previously Fig. 4. The total dose of the salvage radiotherapy (RT)_ for reported therapeutic results for salvage local therapy for the condi- the second oligo-recurrence (OR) (≥51 Gy) tended to tion of OR can be divided into two categories. One is isolated LRR achieve a significantly better overall survival (OS) rate after after disease-free status has been achieved by initial therapy for breast salvage RT for the second OR (P = 0.0561). cancer. The other is isolated distant metastasis after the disease-free status (Table 4)[2–6, 8–10, 17–21]. In most of those results, the lesions of OR conformed to the first OR. However, a subset of once- fourth salvage RT. During the follow-up period, 8 (38%) of the 21 salvaged patients with the first OR may have had second OR. patients were alive without disease, and 6 patients (29%) were alive Selecting this subset of patients for study means that, our selection of with disease. Seven patients (33%) died after second OR. patients for salvage RT is unique. The observed toxicities were mild. Acute toxicities ≥Grade 2 For previously reported clinical outcomes of the isolated LRR as occurred in 10 patients (48%): Grade 3 dermatitis in one patient, the first OR, Table 4 indicates that the 5-year OS ranged from 34% Grade 2 dermatitis in 7 patients, and Grade 2 esophagitis in 2 to 62% after local salvage therapy. Jeong et al. demonstrated the patients. No late toxicities ≥Grade 2 were observed. clinical outcomes for surgery plus postoperative RT or RT alone in The 2-year OS, PFS, and LC (in-field) rates after RT for the 71 cases of breast cancer patients with isolated LRR after mastec- second OR were 83%, 51% and 93%, respectively (Fig. 2). The 3- tomy. Second isolated LRR occurred in 5 (7%) patients, 3 of whom year OS, PFS, and LC (in-field) rates were 65%, 26% and 93%, received surgery and 1 of whom received RT; single-site metastasis respectively. The median survival times (MST) with regard to the occurred in 26 (37%) patients [6]. Those patients were comparable OS and PFS rates after the salvage RT for the second OR were 41 with the patients who experienced second OR. However, the Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 64 � M. Miyata et al. Table 4. Major reports of the local therapy for the oligo-recurrence and the results of the current study in patients with breast cancer Series (Ref.) Year No. of No. of patients Site of Local therapy Treatment outcomes patients with the first OR (%) the OR Isolated LRR Magno [2] 1987 162 162 (100) LRR surgery+RT or RT 5-year OS; 34%, 5-year DFS; 28% Schwaibold [3] 1991 128 128 (100) LRR surgery+RT or RT 5-year OS; 49%, 5-year DFS; 24%, 5-year LRC; 43%, Deutsch [4] 2000 70 70 (100) LRR RT 5-year OS; 36%, CR rate; 87%. Kuo [5] 2008 115 115 (100) LRR surgery+RT or RT 5-year OS; 57%, MST; 106 months, MDFS; 52 months Jeong [6] 2013 71 71 (100) LRR surgery+RT or RT 5-year OS; 62%, MST; 87 months, MDFS; 36 months Isolated DM McDonald [8] 1994 60 60 (100) lung surgery 5-year OS; 38%, MST; 42 months, MDFS; 18 months Planchard [9] 2004 125 125 (100) lung surgery 5-year OS; 45% , MST; 50 months Welter [10] 2008 47 40 (85) lung surgery 5-year OS; 36%, MST; 32 months Milano [11] 2009 40 36 (90) lung SBRT 4-year OS; 59%, 4-year PFS; 38%, 4-year LC; 89% Raab [18] 1998 34 29 (85) liver surgery 5-year OS; 18%, MST; 27 months Selzner [19] 2000 17 14 (82) liver surgery 5-year OS; 22%, MST; 24 months, 5-year DFS; 17% Kondziolka [20] 2011 24 N.A. brain SRS ± WBRT MST 17 months Niibe [21] 2008 7 N.A. bone RT All the patients were alive at the last follow-up. Present study 21 second OR various RT 5-year OS; 34%, MST; 41 months, MPFS; 24 months OR = oligo-recurrence, LRR = loco-regional recurrence, DM = distant metastasis, SBRT = stereotactic body radiotherapy, SRS = stereotactic radiosurgery, WBRT = whole-brain radiotherapy, OS = overall survival, DFS = disease-free survival, LRC = local and/or regional control, CR = complete response, MST = median survival time, MDFS = median disease-free survival, PFS = progression-free survival, MPFS = median progression-free survival, N.A. = not available. Twenty-seven patients were treated with systemic therapy alone. treatment outcomes for the second OR were not described. Kuo OR, the 5-year OS rates after salvage local therapy ranged from et al. also reported that the 5-year OS rate was 57% in 115 patients 18% to 45% (Table 4). McDonald et al. reported the clinical out- with isolated LRR treated with local therapy; 20 (17%) had a comes in 60 patients with pulmonary metastasis treated with surgery second isolated LRR after local therapy, which was comparable with as the first OR, and observed that pulmonary metastases of the a second OR. However, treatment details for the second OR were second OR treated with a second thoracotomy occurred in not stated [5]. In the present study, 7 patients had isolated LRR as 2 patients. One patient had a wedge excision 9 months after the ini- the second OR; they were treated with salvage RT and showed tial pulmonary resection, but expired due to disease recurrence 33 favorable treatment outcomes without severe toxicity; the 2-year months after the second thoracotomy. The other patient had a lob- OS, LC and PFS after salvage RT for the second OR were 100%, ectomy 6.3 years after the initial thoracotomy and is still living 24 100% and 54%, respectively. months later without evidence of disease [8]. Distant metastasis in patients with breast cancer tends to occur Recently, several studies have shown that curative-intent RT in the lung, bone, liver, brain, and lymph nodes [22]. In previously using modern techniques in patients with oligometastatic disease, reported treatment results of those distant metastases as the first including breast cancer, have resulted in good local tumor control Downloaded from https://academic.oup.com/jrr/article-abstract/59/1/58/4647147 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Radiotherapy for second oligo-recurrence � 65 without severe toxicity [23]. Milano et al. reported that a prospect- inducing severe toxicity and is a promising treatment that may result ive study of curative-intent stereotactic RT in patients with 5 or few- in long-term survival in select patients with second OR. Further eva- er oligometastatic lesions at various sites demonstrated that breast luations with detailed treatment protocols are necessary in order to cancer patients had significant improvements in their OS rates; the clarify whether salvage RT could improve survival in breast patients 4-year OS rates in the breast cancer and non-breast cancer patients with second OR. were 54% and 16%, respectively [17]. The same study also reported the clinical outcomes of curative-intent stereotactic RT in 40 CONFLICTOF INTEREST patients with oligometastatic breast cancer; 36 (90%) patients were There are no conflicts of interest. comparable with patients experiencing a first OR; they achieved a 4-year OS of 59% [11]. In the present study, salvage RT for patients with distant metastasis as the second OR also resulted in high local REFERENCES (in-field) control rates. Our results showed a 2-year PFS rate of 1. Siglin J, Champ CE, Vakhnenko Y et al. Radiation therapy for 49%, which was promising, although the OS rates were relatively locally recurrent breast cancer. Int J Breast Cancer 2012;2012: low in comparison to the treatment results of the first OR 571946. (Table 4). 2. Magno L, Bignardi M, Micheletti E et al. Analysis of prognostic In the present study, long-term PFS time and high LC rates factors in patients with isolated chest wall recurrence of breast were observed after salvage RT for the second OR, without severe cancer. Cancer 1987;60:240–4. toxicities. Nevertheless, we believe that additional systemic treat- 3. Schwaibold F, Fowble BL, Solin LJ et al. 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Journal of Radiation ResearchOxford University Press

Published: Jan 1, 2018

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