High-Dose Chemotherapy and Autologous Hematopoietic
Stem Cell Transplantation as Adjuvant Treatment in
High-Risk Breast Cancer: Data from the European Group
for Blood and Marrow Transplantation Registry
Q 5
Massimo Martino
1,*, Francesco Lanza
2, Lorenzo Pavesi
3, Mustafa Öztürk
4, Didier Blaise
5,
Rubén Leno Núñez
6, Harry C. Schouten
7, Alberto Bosi
8, Ugo De Giorgi
9, Daniele Generali
10,
Giovanni Rosti
11, Andrea Necchi
12, Andrea Ravelli
2, Carmelo Bengala
13, Manuela Badoglio
14,
Paolo Pedrazzoli
15, Marco Bregni
16on behalf of the European Group for Blood and Marrow
Transplantation Solid Tumor Working Party
1Hematology and Stem Cell Transplant Unit, Azienda Ospedaliera BMM, Reggio Calabria, Italy
2Section of Hematology and Bone Marrow Transplant Unit, AO Isituti Ospitalieri di Cremona, Cremona, Italy 3Department of Medical Oncology, Fondazione Salvatore Maugeri I.R.C.C.S., Pavia, Italy
4Gulhane Medical Academy, Department of Medical Oncology, General Tevfik Saglam Caddesi, Etlik/Ankara, Turkey 5Department of Hematology, Institut Paoli Calmettes, Marseille, France
6Department of Medical Oncology, Hospital Clínico Universitario, Salamanca, Spain 7Department of Hematology, Academische Ziekenhuis Maastricht, Maastricht, Netherlands
8Hematology Department, Azienda Ospedaliero Universitaria Careggi, University of Florence, Florence, Italy 9Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), Meldola, Italy
10Breast Cancer Unit, AO Isituti Ospitalieri di Cremona, Cremona, Italy 11Department of Medical Oncology, Civil Hospital, Ravenna, Italy
12Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 13Department of Medical Oncology, Misericordia Hospital, Grosseto, Italy
14European Group for Blood and Marrow Transplantation Study Office, Solid Tumors Working Party-EBMT, Hôpital Saint-Antoine, Assistance Publique des Hôpitaux
de Paris, France
15Department of Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation, Pavia, Italy 16Department of Medical Oncology, di Circolo Hospital, Busto Arsizio, Italy
Article history:
Received 18 November 2015 Accepted 17 December 2015 Key Words:
Autologous hematopoietic stem cell transplantation
High-dose chemotherapy High-risk breast cancer
a b s t r a c t
The aim of this retrospective study was to assess toxicity and efficacy of adjuvant high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (AHSCT) in 583 high-risk breast cancer (BC) patients (>3 positive nodes) who were transplanted between 1995 and 2005 in Europe. All patients received surgery before transplant, and 55 patients (9.5%) received neoadjuvant treatment before surgery. Median age was 47.1 years, 57.3% of patients were premenopausal at treatment, 56.5% had endocrine-responsive tumors,19.5% had a human epidermal growth factor receptor 2 (HER2)-negative tumor, and 72.4% had10 positive lymph nodes at surgery. Seventy-nine percent received a single HDC procedure. Overall transplant-related mortality was 1.9%, at .9% between 2001 and 2005, whereas secondary tumor-related mortality was .9%. With a median follow-up of 120 months, overall survival and disease-free survival rates at 5 and 10 years in the whole population were 75% and 64% and 58% and 44%, respectively. Subgroup analysis demonstrated that rates of overall survival were significantly better in patients with endocrine-responsive tumors, <10 positive lymph nodes, and smaller tumor size. HER2 status did not affect survival probability. Adjuvant HDC with AHSCT has a low mortality rate and provides impressive long-term survival rates in patients with high-risk BC. Our results suggest that this treat-ment modality should be considered in selected high-risk BC patients and further investigated in clinical trials. Ó 2015 American Society for Blood and Marrow Transplantation.
Financial disclosure: See Acknowledgments on page 6.
* Correspondence and reprint requests: Massimo Martino, MD, Hema-tology and Stem Cell Transplant Unit, Azienda Ospedaliera BMM, Reggio Calabria, Italy.
E-mail address:maxmartino@live.com(M. Martino).
http://dx.doi.org/10.1016/j.bbmt.2015.12.011
1083-8791/Ó 2015 American Society for Blood and Marrow Transplantation.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126
Biology of Blood and
Marrow Transplantation
j o u r n a l h o m e p a g e : w w w . b b m t . o r g
INTRODUCTION
The efficacy of high-dose chemotherapy (HDC) and
autologous hematopoietic stem cell transplantation (AHSCT) for breast cancer (BC) has been an area of intense controversy
among the medical oncology community [1-3]. Several
phase II studies, conducted throughout the 1980s and early 1990s, suggested that this approach improved long-term
disease control [4-6]. This created great expectations
among physicians and their patients, and HDC with AHSCT
became widely used as a therapeutic option for BC [6].
However, in the early 2000s, due to preliminary reports from randomized studies failing to show improved overall survival (OS) benefit of HDC and a case of scientific misconduct[7], the scene was prematurely set for the demise of HDC in BC [8]. Consequently, the publication of randomized studies
demonstrating an OS benefit by HDC has gone almost
un-noticed in the oncology community[9,10].
In 2011 Berry et al.[11]reported a meta-analysis using data from randomized trials of HDC with AHSCT in high-risk BC patients. Of 6210 patients who participated in the 15 trials, HDC achieved a significant 13% reduction in the risk of recurrence, but this did not translate into a significant OS
benefit despite an apparent improvement of OS in women
with human epidermal growth factor receptor 2 (HER2)-negative disease, which is biologically plausible and sup-ported by clinical data. Meta-analyses have been criticized as blunt instruments, compared with subgroup analyses and individualized therapeutic strategies, by some authors who suggest that HDC might be of potential benefit in subgroups of patients, considering the present limited toxicity of the procedure [1,3,12-14]. As a contribution to this field, we report the results of this approach in a large cohort of pa-tients treated in Europe between 1995 and 2005.
METHODS
The European Group for Blood and Marrow Transplantation (EBMT)
(www.ebmt.org) is a nonprofit organization established in 1974 to allow
scientists and physicians involved in clinical SCT to share their experience and develop cooperative studies. The EBMT is divided into working parties, whose mission is the implementation of EBMT scientific and educational policy, the development and management of scientific proposals with the support of the Data Offices, the development and organization of educa-tional activities with the support of the Executive Office, and assisting the development of definition of guidelines and policies. The Solid Tumor Working Party is dedicated to preclinical, translational, and clinical studies of cell therapy for solid tumors, including AHSCT and allogeneic HSCT, active and adoptive immunotherapy, and lymphoablative therapy with expanded T cells[15,16].
EBMT centers, which are homogenously distributed through European countries, are required to send patient data to the central EBMT database on a yearly basis. There are 2 levels of data: minimal essential data type A, which are compulsory and considered major items, such as demographic data, disease classification, type of transplantation, outcomes, and follow-up; and minimal essential data type B, referring to items sent on a volun-teer basis (type of conditioning or mobilization regimens, complications, number of cells transplanted, etc.).
Study Design
The purpose of the present study was to analyze the EBMT registry data on primary, operable, nonmetastatic BC patients with 4 or more involved nodes at surgery who received HDC and AHSCT between 1995 and 2005 in Europe. The primary outcomes were disease-free survival (DFS) and OS; secondary endpoints were transplantation-related mortality (TRM), non-relapse mortality (NRM), and identification of clinical and biological features that may influence outcome of HDC.
STATISTICS
Probabilities for DFS, OS, and TRM were calculated using the Kaplan-Meier product limit estimate. The log-rank (also called the Mantel-Cox test) and the
Gehan-Breslow-Wilcoxon tests were used for comparisons of DFS and OS between groups [17,18]; stratifying parameters included menopausal status, age, hormone receptor (HR) status (es-trogen or progesterone receptor positive versus both nega-tive), HER2 status (positive versus neganega-tive), number of positive lymph nodes, primary tumor categories, and mul-tiple versus single HDC. The log-rank test is the more powerful of the 2 tests if the assumption of proportional hazards is true. Proportional hazards means that the ratio of hazard functions (deaths per time) is the same at all time points. The Gehan-Breslow-Wilcoxon method gives more weight to deaths at early time points.
DFS and OS rates were measured from the date of surgery to the date of last follow-up or death and the date of relapse, respectively. TRM was defined as mortality from any cause other than disease progression within 365 days of
trans-plantation. NRM was defined as mortality from any cause
other than disease progression or TRM, after the trans-plantation. Before starting the present analysis, EBMT centers were contacted for missing data.
All P values were 2-sided, and a P< .05 was considered statistically significant. Statistical calculations were car-ried out by using SAS software (version 9.2; SAS Institute, Cary, NC).
RESULTS
Among adjuvant patients with BC reported in the EBMT registry, 583 patients with 4 or more involved nodes at surgery were available for OS analysis and represent the body of this article. Informed consent to collect and register data to the EBMT record was obtained from participants. The baseline patient and treatment characteristics are
summarized in Table 1. The median patient age was
47.1 years (range, 22.4 to 66.5), and 57.3% of women were premenopausal. Data on HR status and HER2 status were available in 84.7% and 31.4% of patients, respectively. In-formation for defining triple-negative (TN) BC (ie, tumors that lack estrogen receptor, progesterone receptor, and HER2 overexpression) was available in only 35 patients. Approximately 18% of patients had breast masses larger than 5 cm. The median number of lymph nodes involved at surgery was 13 (range, 4 to 46), and the number of patients having 4 to 9, 10 to 19, and>20 pathologic nodes was 27.6%, 52.4%, and 20%, respectively.
Virtually all AHSCTs were performed using mobilized peripheral blood hematopoietic progenitor cells (>95%). All patients received granulocyte colony-stimulating factor support after transplantation; 20.8% underwent HDC more than once.
The conditioning regimens included only alkylating agents in 73% of cases, whereas antaracyclinesor mitoxan- Q 1
trone were used in 27% of cases. Either thiotepa of melphalan were included in most conditioning regimens.
In 55 patients (9.5%) harboring T4 disease (tumor of any size with direct extension to the chest wall and/or to the skin) and/or node-postitve clinical involvement (metastases to movable ipsilateral level I, II axillary lymph node(s) at presentation), a single HDC after conventional-dose chemo-therapy was performed before surgery as neoadjuvant ther-apy. Conventional anthracycline-based or, in more recent years, anthracycline/taxane-based adjuvant chemotherapy always preceded HDC. Among patients with HR-positive tumors, most received tamoxifen after HDC. Radiotherapy was administered after completion of chemotherapy, in accordance with local recommendations.
127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256
DFS and OS Estimates
Kaplan-Meier curves of DFS and OS for the whole study
population are shown in Figure 1A and B. With a median
follow-up of 10 years, DFS was 7.2 years, with 64% and 44% of patients free of disease at 5 and 10 years, respectively. Median OS was not reached, with 75% and 58% of the pa-tients alive 5 and 10 years after transplantation. Age (<40 versus>40 to 50 versus >50 years) (Figure 2A), menopausal status (Figure 2B), and single versus multiple HDC did not affect survival.
We found that survival was statistically better for patients with smaller size (<2 cm, 5-year survival probability of 78% and 10-year survival probability of 69%) as compared with those with sizes ranging from 2 to 5 cm (5-year survival probability of 73% and 10-year survival probability of 57%) and size > 5 cm (5-year survival probability of 63% and 10-year survival probability of 50%) (log rank test P¼ .04; Breslow test P¼ .02) (Figure 3A). Similarly, the cumulative survival was better in patients with tumor grading 1 to 2 (5-year survival probability of 79% and 10-year survival probability of 59%) compared with those with grade 3.4 (5-year survival probability of 65% and 10-year survival probability of 55%) (log rank test P ¼ .068; Breslow test P¼.010) (Figure 3B). The cumulative survival at 5 and 10 years was 78% and 61% in patients with HR-positive tumor and 64%
and 55% in patients with HR-negative tumor, respectively (log rank test P¼ .04; Breslow test P ¼ .01) (Figure 4).
Patients with 4 to 9 positive axillary nodes had 84% and 66% survival probability at 5 and 10 years, respectively. These figures decreased approximately by 10% for patients with 10 to 19 positive nodes and by a further 10% for patients with 20 or more positive nodes (log rank test P¼ .0007; Breslow test P¼ .0004;Figure 5). In patients harboring TN tumors, rates of DFS and OS at 5 and 10 years were 51% and 37% and 60% and 52%, respectively.
In a multiple Cox regression model including HR status, number of positive lymph nodes, and tumor size, only number of positive lymph nodes maintained an independent relationship with mortality (hazard ratio, 1.76; 95% con fi-dence interval, 1.20 to 2.60; P¼ .004). The other 2 remaining variables were not significant (P ¼ .11 to .18).
Toxicity and Secondary Malignancies
Because of the limited information provided by the minimal essential data type A form, detailed information on acute morbidity, including grade of mucositis and occurrence of infection, cannot be provided. Treatment-induced meno-pause, defined as >2 years of amenorrhea after HDC with no resumption of menses, was reported in a large proportion of patients who were premenopausal at the time of diagnosis. Neutrophil and platelet recovery occurred in all but 5 pa-tients who died before engraftment from infections. Overall TRM occurred in 11 of 583 cases (1.9%), at .9% between 2001
and 2005. Ten patients died in the first 100 days
post-transplantation, and 1 patient with inactive hepatitis B died 8 months after transplantation from an abrupt increase in hepatitis B virus replication. NRM was 2.9% (17/583) and consisted of heart failure (5/583, .9%), on-road traffic acci-dents (2/583, .3%), suicide (1/583, .2%), unknown causes (4/583, .6%), and second neoplasia (5/583, .9% [4 solid tumors and 1 acute leukemia]).
DISCUSSION
The present study, reporting a retrospective data analysis on HDC and AHSCT for high-risk BC in Europe, includes 1 of the largest series in thisfield. Because it comes from a reg-istry and derives from patients transplanted in many cases when only limited information on tumor biology was avail-able, many parameters are lacking, making interpretation of results more difficult[19,20].
Patients included in the present analysis were selected if they had at least 4 positive lymph nodes. In the absence of other factors, mainly HER2 status, axillary node involvement was the major negative prognostic factor for recurrence[11] and was thus used to identify patients at high risk of recur-rence to be selected for studies in the adjuvant setting.
Our results showed that adjuvant HDC with AHSCT, in contrast with early studies[21,22], is a safe procedure with a TRM that is, in more recent years, inferior to 1%. This is consistent with what has been observed in modern pro-spective studies[9,10]. Furthermore, in keeping with pre-vious reports[11,19,20], the long-term effects of HDC do not differ from those observed with conventional chemo-therapy, in particular regarding the risk of secondary cancer [11,23,24].
Survival rates in our study appear to be impressive when considering that all patients, including patients who received primary chemotherapy, had>3 positive nodes at surgery. Importantly, patients with more than 9 pathologic nodes were the vast majority (72.4%); this population has an
Table 1
Patient Demographic, Clinical, and Treatment Characteristics Characteristic No. Patients
(N¼ 586)
Percent Median age, yr (range) 47.1 (22.4-66.5)
<40 138 23.6 40-50 241 41.1 >50 207 35.3 Menopausal status Premenopausal 336 57.3 Postmenopausal 181 31.0 Missing information 69 11.7 HR status Negative 165 28.2 Positive 331 56.5 Missing information 90 15.3 HER2 status Negative 114 19.5 Positive 70 11.9 Missing information 402 68.6 Positive lymph nodes
4-9 162 27.6 10-19 307 52.4 20 117 20.0 Tumor size, cm <2 134 22.9 2-5 295 50.3 >5 102 17.4 Missing information 55 9.4 Grading 1-2 173 35.6 3-4 283 42.3 Missing information 130 22.1 Median no. of cycles of conventional
chemotherapy before AHSCT (range)
4 (0-10) Containing anthracyclines 84.1 Containing taxanes/anthracyclines 25.0 Neoadjuvant therapy 9.3 AHSCT with peripheral blood as source of
stem cells
>95
Single AHSCT 79.2
Multiple AHSCT 20.8
Conditioning regimen
Alkylating agents only 73 Including anthracyclines or mitoxantrone 27
257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386
extremely poor prognosis and is usually present in very limited number in BC adjuvant studies. In keeping with both the important prognostic role of axillary node involvement, which is independent of biological parameters, together with
the results of previous studies[10,19], the number of positive nodes indeed negatively affected OS in our series.
In our study age and menopause had no impact on outcome. However, many premenopausal women became
Figure 1. Kaplan-Meier curve of (A) DFS and (B) OS for the whole study population.
Q 6
Figure 2. Kaplan-Meier estimates of OS in prespecified subset analyses by (A) age at surgery and (B) menopause status.
387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516
persistently amenorrheic after HDC[9], and this may obscure any effects on outcome.
Patients with HR-positive BC had a significantly better survival. Positivity for HR is a known positive prognostic factor, characterized usually by more indolent disease. This allows hormonal targeted therapy after recovery from HDC, an opportunity that may have further influenced these re-sults. Improved outcomes for HR-positive versus HR-negative disease is a recurrent feature in most HDC series [9,19,25].
More surprising is the more pronounced beneficial effect of HDC in small and low-grade tumors, which might be simply related to the better outcome of such populations. However, because it is known that a subgroup of luminal BC tumors that do not seem to be aggressive based on their immunohisto-chemical phenotype has a bad prognosis, HDC might have played a positive role in these tumors[26,27].
HER2-positive status did not affect DFS and OS in our series, in contrast with previous reports[10,28]. However,
Figure 3. Kaplan-Meier estimates of OS in prespecified subset analyses by (A) tumor size and (B) tumor grading.
Figure 4. Kaplan-Meier estimates of median OS according to tumor HR status. 95% CI indicates 95% confidence interval.
517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646
the survival curves diverge quite markedly in favor of the HER-negative group, suggesting that the lack of a statis-tically significant survival benefit might be in part related to the fact that only 32.4% of patients had HER2 status available. Therefore, the analysis was conducted in a limited proportion of our patients. A large Dutch study
[10] showed greater DFS and OS in their HER2-negative
population, and the authors suggested that the dose of anthracycline in patients harboring HER2-positive tumors should be increased. In our studies a significant number of HDC regimens included anthracyclines, mitoxantrone, and/or the introduction of anti-HER2 drugs in the adjuvant or metastatic phase. This may explain some differences from other series.
Unfortunately, TN disease was documented in only 35 patients, so the apparent beneficial results obtained in this high-risk population are largely insufficient to generate any hypothesis. However, Gluz et al.[28]found that the benefit of HDC was more evident in a basal-like phenotype (estrogen and progesterone receptor negative, HER2 negative, and basal cytokeratin positive) and in grade 3 tumors. Other authors have speculated that patients with TN tumors are the most likely to receive a benefit from HDC, because these cancers do not respond to endocrine therapy or other avail-able targeted agents. The metastatic potential in TN BC is similar to that of other BC subtypes, but these tumors are associated with a shorter median time to relapse and death, as is also demonstrated in our small cohort.
Today, HDC with AHSCT has become a safe treatment modality with mortality rates[9,19,20]and quality-adjusted survival parameters[29]similar to conventional therapies. TRM and morbidity has progressively decreased from the mid-1990s, possibly related to the widespread switch from bone marrow hematopoietic progenitor cells to peripheral blood hematopoietic progenitor cells[30]and a better un-derstanding of the whole procedure and supportive mea-sures [31,32]. Moreover, HDC regimens associated with a high TRM are no longer used.
Most of the oncology community believes that HDC is no longer applicable now that we have entered the era of tar-geted therapies. Such a conclusion could be premature because the prognosis of high-risk BC has changed very little in the past 2 decades and particular novel targeted therapies have had an impact only in the subset of patients with BC overexpressing HER2. Moreover, in high-risk BC, 2 large European studies demonstrated an OS benefit of HDC
consistent with the benefit in the HER2-ve and TN pop- Q 2
ulations[9,10,28]. In the adjuvant setting of BC, a survival benefit, although limited, still means thousands of women being cured.
In conclusion, our study confirms that HDC and AHSCT in high-risk BC can now be given safely and with the needed dose intensification, with minimal early and late toxicity. Along with some more recent phase III studies, retrospec-tive analyses, and, to some extent, the results from meta-analyses, our results suggest a potential role for HDC and AHSCT in high-risk BC. This approach may still represent a therapeutic option for carefully selected patients who har-bor HER2-negative tumors and who have gross involvement of axillary lymph nodes. Further studies of HDC are advis-able, taking into account the clinical and biological infor-mation we currently have, to select and target those patients more likely to benefit from chemotherapy given at higher than standard doses.
ACKNOWLEDGMENTS
Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of in-terest to report.
Authorship statement: M.M., F.L., C.B., P.P., and M.Br. designed the study. M.M., F.L., G.R., C.B., M.Ba., P.P., and M.Br. performed quality control of data and algorithms. M.M., F.L., D.G., G.R., C.B., and P.P. conducted data analysis and inter-pretation. M.M., F.L., and P.P. performed statistical analysis. M.M., F.L., D.G., and P.P. prepared the manuscript. M.M., F.L., D.G., C.B., and P.P. edited the manuscript. All authors
Figure 5. Kaplan-Meier estimates of median OS according to number of positive lymph nodes at surgery.
647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776
reviewed the manuscript and approved the submitted and final versions.
REFERENCES
1. Pedrazzoli P, Martino M, Delfanti S, et al. High-dose chemotherapy with autologous hematopoietic stem cell transplantation for high-risk primary breast cancer. J Natl Cancer Inst Monogr. 2015;70-75.
Q 3
2. Hortobagyi GN. What is the role of high-dose chemotherapy in the era of targeted therapies? J Clin Oncol. 2004;22:2263-2266.
3. Castagna L, Martino M. Are there still reasons to believe that high-dose chemotherapy has a role in breast cancer management? Bone Marrow Transplant. 2013;48:305.
4. Peters WP, Ross M, Vredenburgh JJ, et al. High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol. 1993;11:1132-1143.
5. Gianni AM, Siena S, Bregni M, et al. Efficacy, toxicity, and applicability of high-dose sequential chemotherapy as adjuvant treatment in operable breast cancer with 10 or more involved axillary nodes: five-year results. J Clin Oncol. 1997;15:2312-2321.
6. Pedrazzoli P, Ferrante P, Kulekci A, et al. Autologous hematopoietic stem cell transplantation for breast cancer in Europe: critical evalua-tion of data from the European Group for Blood and Marrow Trans-plantation (EBMT) Registry 1990-1999. Bone Marrow Transplant. 2003; 32:489-494.
7. Weiss RB, Rifkin RM, Stewart FM, et al. High-dose chemotherapy for high-risk primary breast cancer: an on-site review of the Bezwoda study. Lancet. 2000;355:999-1003.
8. Passweg JR, Baldomero H, Bader P, et al. Hematopoietic SCT in Europe 2013: recent trends in the use of alternative donors showing more haploidentical donors but fewer cord blood transplants. Bone Marrow Transplant. 2015;50:476-482.
9. Nitz UA, Mohrmann S, Fischer J, et al. Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial. Lancet. 2005;366:1935-1944.
10. Rodenhuis S, Bontenbal M, van Hoesel QG, et al. Efficacy of high-dose alkylating chemotherapy in HER2/neu-negative breast cancer. Ann Oncol. 2006;17:588-596.
11. Berry DA, Ueno NT, Johnson MM, et al. High-dose chemotherapy with autologous stem-cell support as adjuvant therapy in breast cancer: overview of 15 randomized trials. J Clin Oncol. 2011;20:3214-3223. 12. De Giorgi U, Amadori D. Dose intensification in hormone
receptor-negative and/or human epidermal growth factor receptor 2-receptor-negative high-risk primary breast cancer. J Clin Oncol. 2012;30:758.
13. Moroni M. High-dose chemotherapy as adjuvant therapy in breast cancer: could there be a survival benefit? J Clin Oncol. 2012;30:759. 14. Wang J, Zhang Q, Zhou R, et al. High-dose chemotherapy followed by
autologous stem cell transplantation as afirst-line therapy for high-risk primary breast cancer: a meta-analysis. PLoS One. 2012;7:e33388. 15. Peccatori J, Barkholt L, Demirer T, et al. Prognostic factors for survival in patients with advanced renal cell carcinoma undergoing non-myeloablative allogeneic stem cell transplantation. Cancer. 2005;104: 2099-2103.
16. Ueno NT, Rizzo JD, Demirer T, et al. Allogeneic hematopoietic cell transplantation for metastatic breast cancer. Bone Marrow Transplant. 2008;41:537-545.
17. Harrington D. Linear rank tests in survival analysis. Encyclopedia of biostatistics. Wiley Interscience; 2005. Q 4
18. McCullagh P, Nelder JA. Generalized linear models (Chapman & Hall/CRC monographs on statistics & applied probability), 2nd ed. London, UK: Chapman & Hall; 1989.
19. Pedrazzoli P, Martinelli G, Gianni AM, et al. Adjuvant high-dose chemotherapy with autologous hematopoietic stem cell support for high-risk primary breast cancer: results from the Italian national reg-istry. Biol Blood Marrow Transplant. 2014;20:501-506.
20. Martino M, Ballestrero A, Zambelli A, et al. Long-term survival in pa-tients with metastatic breast cancer receiving intensified chemo-therapy and stem cell rescue: data from the Italian registry. Bone Marrow Transplant. 2013;48:414-418.
21. Tallman MS, Gray R, Robert NJ, et al. Conventional adjuvant chemo-therapy with or without high-dose chemochemo-therapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med. 2003; 349:17-26.
22. Peters WP, Rosner GL, Vredenburgh JJ, et al. Prospective, randomized comparison of high-dose chemotherapy with stem-cell support versus intermediate-dose chemotherapy after surgery and adjuvant chemo-therapy in women with high-risk primary breast cancer: a report of CALGB 9082, SWOG 9114, and NCIC MA-13. J Clin Oncol. 2005;23: 2191-2200.
23. Kröger N, Damon L, Zander AR, et al. Secondary acute leukemia following mitoxantrone-based high-dose chemotherapy for primary breast cancer patients. Bone Marrow Transplant. 2003;32:1153-1157. 24. Berry DA, Ueno NT, Johnson MM, et al. High-dose chemotherapy with
autologous hematopoietic stem-cell transplantation in metastatic breast cancer: overview of six randomized trials. J Clin Oncol. 2011;29: 3224-3231.
25. International Breast Cancer Study Group, Basser RL, O’Neill A, Martinelli G, et al. Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95. J Clin Oncol. 2006;24:370-378. 26. Szekely B, Iwamoto T, Szasz AM, et al. A 3-gene proliferation score
(TOP-FOX-67) can re-classify histological grade-2, ER-positive breast cancers into low- and high-risk prognostic categories. Breast Cancer Res Treat. 2013;138:691-698.
27. Markiewicz A, Wełnicka-Jaskiewicz M, Skokowski J, et al. Prognostic significance of ESR1 amplification and ESR1 PvuII, CYP2C19*2, UGT2B15*2 polymorphisms in breast cancer patients. PLoS One. 2013; 8:e72219.
28. Gluz O, Nitz UA, Harbeck N, et al. Triple-negative high-risk breast cancer derives particular benefit from dose intensification of adjuvant chemotherapy: results of WSG AM-01 trial. Ann Oncol. 2008;19: 861-870.
29. Marino P, Roché H, Moatti JP, et al. High-dose chemotherapy for pa-tients with high-risk breast cancer: a clinical and economic assessment using a quality-adjusted survival analysis. Am J Clin Oncol. 2008;31: 117-124.
30. Siena S, Bregni M, Di Nicola M, et al. Durability of hematopoiesis following autografting with peripheral blood hematopoietic pro-genitors. Ann Oncol. 1994;5:935-941.
31. Körbling M, Fliedner TM. The evolution of clinical peripheral blood stem cell transplantation. Bone Marrow Transplant. 1996;17: 675-678.
32. Antman KH, Rowlings PA, Vaughan WP, et al. High-dose chemotherapy with autologous hematopoietic stem-cell support for breast cancer in North America. J Clin Oncol. 1997;15:1870-1879.
777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 920 921 922 923 924 925 926 927 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946
