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Breast cancer follow-up strategies in randomized phase III adjuvant clinical trials: a systematic review
Journal of Experimental & Clinical Cancer Research volume 32, Article number: 89 (2013)
The effectiveness of different breast cancer follow-up procedures to decrease breast cancer mortality are still an object of debate, even if intensive follow-up by imaging modalities is not recommended by international guidelines since 1997. We conducted a systematic review of surveillance procedures utilized, in the last ten years, in phase III randomized trials (RCTs) of adjuvant treatments in early stage breast cancer with disease free survival as primary endpoint of the study, in order to verify if a similar variance exists in the scientific world. Follow-up modalities were reported in 66 RCTs, and among them, minimal and intensive approaches were equally represented, each being followed by 33 (50%) trials. The minimal surveillance regimen is preferred by international and North American RCTs (P = 0.001) and by trials involving more than one country (P = 0.004), with no relationship with the number of participating centers (P = 0.173), with pharmaceutical industry sponsorship (P = 0.80) and with trials enrolling > 1000 patients (P = 0.14). At multivariate regression analysis, only geographic location of the trial was predictive for a distinct follow-up methodology (P = 0.008): Western European (P = 0.004) and East Asian studies (P = 0.010) use intensive follow-up procedures with a significantly higher frequency than international RCTs, while no differences have been detected between North American and international RCTs. Stratifying the studies according to the date of beginning of patients enrollment, before or after 1998, in more recent RCTs the minimal approach is more frequently followed by international and North American RCTs (P = 0.01), by trials involving more than one country (P = 0.01) and with more than 50 participating centers (P = 0.02). It would be highly desirable that in the near future breast cancer follow-up procedures will be homogeneous in RCTs and everyday clinical settings.
In the last years, a substantial increase in the number of women surviving breast cancer , the most frequent female cancer in the world [2–5], has been reported. This leads to the necessity to focus on breast cancer follow-up procedures for the high relevance they have for both patients and professional personnel . The primary aim of routine post-operative surveillance after early stage breast cancer surgery, referred to as 'follow-up’, is to enhance survival, psychosocial and physical well-being of patients. The effectiveness of different breast cancer follow-up procedures for early detection of metastatic disease is an old issue, starting in the 1980s [7–10]. In the 1990s, evidences from phase III randomized trials (RCTs) demonstrated that intensive follow-up procedures do not improve outcome or quality of life when compared to patients’ educations about symptoms referral and regular physical examinations [11–18]. Nowadays, there is a general agreement on the utility of yearly mammography for detecting local recurrences and/or second primary cancers while intensive follow-up practices by imaging techniques (i.e. chest radiograph, bone scan and liver sonography) are not recommended by current international guidelines [19, 20]. Nevertheless, the appropriateness of screening tests to be used as well as the frequency of follow-up procedures and the optimal follow-up duration are still object of debate [21–24], which reflects in the wide use of intensive surveillance and in the long-term follow-up period in everyday clinical practice [6, 25–28].
Based on these premises, we conducted a systematic review of the surveillance procedures utilized in phase III RCTs of adjuvant treatments in early stage breast cancer in order to asses if a similar variance exists in the scientific world.
Literature search and eligibility criteria
We searched PubMed (PubMed, available at URL: http://www.ncbi.nlm.nih.gov/pubmed) from January 1, 2002 to December 31, 2012 for phase III RCTs of early breast cancer medical adjuvant therapies with disease free survival (DFS) as primary endpoint of the study . We selected only full text publications (not abstracts), written in English-language. Trials on neoadjuvant therapies, neoadjuvant followed by adjuvant therapies, adjuvant bisphosphonates alone, non medical treatments, radiation therapies, adjuvant chemotherapy for loco-regional relapses and non-phase III trials were excluded. When multiple publications of the same RCT were identified, the first publication was selected. We used as keywords: breast cancer adjuvant therapy, clinical trial, phase III, phase 3 and randomized.
Information extracted from each trial included: date of beginning of patients enrollment, geographic location, number of participating countries, sponsorship by pharmaceutical companies, number of participating centers, number of enrolled patients, follow-up description (modalities, frequency and duration). Follow-up was classified as minimal when only history/physical examination and/or automated blood chemistry studies, and intensive when chest radiographs ± bone scan ± liver sonography ± tumor markers were included. Screening and data extraction were performed independently by two investigators.
Descriptive statistics were used to report relevant study information. The associations between variables and follow-up data were tested by the Pearson’s chi-square test or Fisher’s exact test, as appropriate. All p values are reported as 2-sided and p values less than 0.05 denotes statistically significant association. A multiple correspondence analysis (MCA), an exploratory multivariate statistical technique, was used to analyze possible relationships among all variables and identify specific profiles . In the MCA, associations between variables are displayed graphically as maps, and their position in the graphic is exclusively informative. The prediction of follow-up procedures was evaluated using a stepwise multivariate logistic regression. The cut-off p value for inclusion or exclusion in the model was set at 0.10 and 0.15, respectively. The Odds Ratio (OR) and the 95% confidence intervals (95% CI) were estimated for each variable. The SPSS software (SPSS version 19.0, SPSS Inc., Chicago, Illinois, USA) was used for all statistical evaluations.
Of 441 potentially relevant abstracts identified, 98 papers met full inclusion criteria: follow-up modalities were reported in 66 RCTs [31–95] while no information was given in the remaining 32 [96–127]. Two different trials, the ABCSG trial 8 and ARNO 95 trial, are reported in the same paper by Jakesz et al. . The flowchart of search strategy is shown in Figure 1.
As shown in Table 1, there is a trend towards more frequently describing surveillance procedures in papers from international, West European or East Asian (Japan, Vietnam and China) RCTs than in those from North American (USA and Canada) RCTs (P = 0.06); no relationship has been found between other variables taken into account and the availability of follow-up data.
Among the 66 papers describing follow-up methodology, minimal and intensive approaches were equally represented, each being followed by 33 (50%) trials. Only 6 papers report the use of tumor markers measurement (carcinoembryonic antigen and carbohydrate antigen 15–3) during follow-up [46, 48, 57, 75, 82, 88] and none includes the use of computed tomography scans, positron emission tomography scanning and magnetic resonance imaging.
Table 2 shows that the minimal surveillance regimen is preferred by international and North American RCTs (P = 0.001) and by trials involving more than one country (P = 0.004), while there is no relationship with the number of participating centers (P = 0.173), the pharmaceutical industry sponsorship (P = 0.80), trials enrolling > 1000 patients (P = 0.14). Breast cancer follow-up guidelines, recommending the minimal approach, were published by the American Society of Clinical Oncology in 1997 . Interestingly, no differences in follow-up modalities have been detected in RCTs enrolling patients before and after 1998 (P = 0.58). Stratifying data according to the date of beginning of patients enrollment (i.e. before or after 1998), even if numbers are small, in more recent studies there is a higher use of the minimal approach by international and North American RCTs (P = 0.01) and by trials involving more than one country (P = 0.01), and more than 50 participating centers (P = 0.02), with a trend toward statistical significance for trials enrolling > 1000 patients (P = 0.06) (Table 3).
The graphical map of MCA (Figure 2) shows that intensive follow-up procedures cluster with Western European and East Asian studies, studies with less than 50 participating centers and less than 1000 enrolled patients, and with patients enrollment beginning before 1998, while the minimal approach clusters with RCTs enrolling more than 1000 patients and beginning enrollment after 1998 (Figure 2). At multivariate regression analysis, only geographic location of the trial was predictive for a distinct follow-up methodology (P = 0.008). In particular, setting as a reference the international studies, Western European (P = 0.004) and East Asian studies (P = 0.010) use intensive follow-up procedures with a significantly higher frequency than international RCTs, while no differences are detected between North American and international RCTs.
For each follow-up approach, the frequency at which the different exams are performed is highly variable, ranging from 1 to 4 times/year for history and/or physical examinations, and from 1 to 3 times/year for imaging modalities, as shown in Table 4. Almost all RCTs showed the highest number of evaluations/year in the first 1–2 years of follow-up; 5-year follow-up and annually thereafter was chosen by almost all studies, with the following exceptions: two studies interrupted all imaging modalities at the 3rd year [83, 84]; one study discontinued chest radiographs and bone scan at the 4th year  and one study ended chest radiographs at the 3rd year .
The results of our systematic review demonstrates that among phase III RCTs of adjuvant therapies for early stage breast cancer, minimal and intensive follow-up approaches are equally used. However, it should be noted that not all the papers, mainly from North America, report the modalities of follow-up [91–121], even if we selected RCTs with primary endpoint represented by DFS, which can be affected by the surveillance methodologies applied. Possible explanations could be that i) the authors and referees do not think this is a relevant issue or ii) a follow-up according to established guidelines was applied, thus making it unnecessary to specify. The second hypothesis may be more likely, since the minimalist follow-up suggested by international guidelines is more frequently followed by North American while intensive follow-up is preferred by Western European and East Asian trialists.
Our analysis also suggests that the use of the different strategies of follow-up is not dictated by the necessity of costs containment as it has been suggested [129–131], since no relationship with industrial sponsorships, number of participating centers and number of enrolled patients has been found. It seems more likely that the intensive surveillance methodology in RCTs follows Western European and East Asian cultural attitudes of scientists and medical oncologists towards the care of breast cancer patients . In this respect, it has recently been reported that many European and East Asian breast cancer patients receive more intensive follow-up care than recommended by the current guideline [6, 25, 26, 133, 134] even if, at a lesser extent, this has been also reported for American and Canadian patients [27, 28].
The frequency of follow-up is higher in the first 2–3 years after surgery and tends to decrease thereafter. Almost all RCTs, except few studies [46, 83, 84], continue programmed controls at least 5 years after treatment, independently from the chosen follow-up methodology. These issues are still object of debate , since neither the optimum frequency nor duration of follow-up has been clearly defined [23, 136, 137].
Results from two Italian phase III RCTs, both published in 1994 [11, 12] and several retrospective studies [138–141] demonstrated that intensive follow-up strategies including chest radiography, bone scan, liver ultrasound and tumor markers measurements do not improve survival as compared to history taking, physical examinations and annual mammography. On the basis of these data, the American Society of Clinical Oncology published in 1997 and periodically updated thereafter [19, 128, 142] breast cancer follow-up guidelines recommending a minimal approach. We found no increase in the use of minimalist follow-up among RCTs beginning to enroll patients one year after published guidelines (i.e. 1998). However, more recently the minimal approach is being preferred by most international and North American RCTs, and bigger trials, such as those involving more than one country and more than 50 participating centers. It is relevant to point up that the use of the intensive follow-up is still present in almost 45% of new generation RCTs.
A possible limit of our study may be represented by the choice of studies written in English, although the vast majority of RCTs are currently published in this language and in scientific journal indexed in PubMed. In addition, it should be underlined that it is likely the statistic analysis could be not completely reliable, considering that in some of the subcategories considered in the study, the number of eligible RCTs is low.
Current breast cancer follow-up guidelines, which are based on RCTs, suggest a minimal follow-up approach for surveillance of early breast cancer patients, but this suggestion is not widely applied neither in phase III RCTs of adjuvant treatments nor in real world clinical practice. Whether the minimal follow-up approach will still be the recommended option in the future, is to be confirmed. In fact, more effective and sophisticated diagnostic procedures may be useful to point out severe long-term side effects of new molecularly targeted agents as well as an early detection of oligometastatic disease might be suitable for cure with newer therapeutic strategies, as it has been suggested for other neoplasms . Finally, it would be highly desirable that in the near future the follow-up procedures will be homogeneous in RCTs and everyday clinical settings.
Disease free survival
Multiple correspondence analysis
Randomized clinical trials.
De Angelis R, Tavilla A, Verdecchia A, Scoppa S, Hachey M, Feuer EJ, Mariotto AB: Breast cancer survivors in the United States: geographic variability and time trends, 2005–2015. Cancer. 2009, 115 (9): 1954-1966.
Siegel R, Naishadham D, Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 2013, 63 (1): 11-30.
Piscitelli P, Barba M, Crespi M, Di Maio M, Santoriello A, D’Aiuto M, Fucito A, Losco A, Pentimalli F, Maranta P, et al: The burden of breast cancer in Italy: mastectomies and quadrantectomies performed between 2001 and 2008 based on nationwide hospital discharge records. J Exp Clin Cancer Res. 2012, 31: 96-104.
Vrdoljak E, Wojtukiewicz MZ, Pienkowski T, Bodoky G, Berzinec P, Finek J, Todorovic V, Borojevic N, Croitoru A: Cancer epidemiology in Central, South and Eastern European countries. Croat Med J. 2011, 52 (4): 478-487.
Australian Institute of Health and Welfare: Cancer in Australia: Actual incidence data from 1991 to 2009 and mortality data from 1991 to 2010 with projections to 2012. Asia Pac J Clin Oncol. 2013, 9 (3): 199-213.
van Hezewijk M, Hille ET, Scholten AN, Marijnen CA, Stiggelbout AM, van de Velde CJ: Professionals’ opinion on follow-up in breast cancer patients; perceived purpose and influence of patients’ risk factors. Eur J Surg Oncol. 2011, 37 (3): 217-224.
Arnstein NB, Harbert JC, Byrne PJ: Efficacy of bone and liver scanning in breast cancer patients treated with adjuvant chemotherapy. Cancer. 1984, 54 (10): 2243-2247.
Evans DM, Wright DJ: The role of bone and liver scans in surveying patients with breast cancer for metastatic disease. Am Surg. 1987, 53 (10): 603-605.
Feig SA: Imaging techniques and guidelines for evaluation and follow-up of breast cancer patients. Crit Rev Diagn Imaging. 1987, 27 (1): 1-16.
Kunkler IH, Merrick MV, Rodger A: Bone scintigraphy in breast cancer: a nine-year follow-up. Clin Radiol. 1985, 36 (3): 279-282.
The GIVIO Investigators: Impact of follow-up testing on survival and health-related quality of life in breast cancer patients. A multicenter randomized controlled trial. JAMA. 1994, 271 (20): 1587-1592.
Rosselli Del Turco M, Palli D, Cariddi A, Ciatto S, Pacini P, Distante V: Intensive diagnostic follow-up after treatment of primary breast cancer. A randomized trial. National Research Council Project on Breast Cancer follow-up. JAMA. 1994, 271 (20): 1593-1597.
Rojas MP, Telaro E, Russo A, Fossati R, Confalonieri C, Liberati A: Follow-up strategies for women treated for early breast cancer. Cochrane Database Syst Rev. 2000, 4: CD001768
Rojas MP, Telaro E, Russo A, Moschetti I, Coe L, Fossati R, Palli D, del Roselli TM, Liberati A: Follow-up strategies for women treated for early breast cancer. Cochrane Database Syst Rev. 2005, 1: CD001768
Grunfeld E, Fitzpatrick R, Mant D, Yudkin P, Adewuyi-Dalton R, Stewart J, Cole D, Vessey M: Comparison of breast cancer patient satisfaction with follow-up in primary care versus specialist care: results from a randomized controlled trial. Br J Gen Pract. 1999, 49 (446): 705-710.
Grunfeld E, Mant D, Yudkin P, Adewuyi-Dalton R, Cole D, Stewart J, Fitzpatrick R, Vessey M: Routine follow up of breast cancer in primary care: randomised trial. BMJ. 1996, 313 (7058): 665-669.
Gulliford T, Opomu M, Wilson E, Hanham I, Epstein R: Popularity of less frequent follow up for breast cancer in randomised study: initial findings from the hotline study. BMJ. 1997, 314 (7075): 174-177.
Palli D, Russo A, Saieva C, Ciatto S, Rosselli Del Turco M, Distante V, Pacini P: Intensive vs clinical follow-up after treatment of primary breast cancer: 10-year update of a randomized trial. National Research Council Project on Breast Cancer Follow-up. JAMA. 1999, 281 (17): 1586-
Khatcheressian JL, Hurley P, Bantug E, Esserman LJ, Grunfeld E, Halberg F, Hantel A, Henry NL, Muss HB, Smith TJ, Vogel VG, Wolf AC, Somerfield MR, Davidson NE, American Society of Clinical Oncology: Breast cancer follow-up and management after primary treatment: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013, 31 (7): 961-965.
Grunfeld E, Dhesy-Thind S, Levine M: Clinical practice guidelines for the care and treatment of breast cancer: follow-up after treatment for breast cancer (summary of the 2005 update). CMAJ. 2005, 172 (10): 1319-1320.
Montgomery DA, Krupa K, Cooke TG: Follow-up in breast cancer: does routine clinical examination improve outcome? A systematic review of the literature. Br J Cancer. 2007, 97 (12): 1632-1641.
de Bock GH, Bonnema J, van der Hage J, Kievit J, van de Velde CJ: Effectiveness of routine visits and routine tests in detecting isolated locoregional recurrences after treatment for early-stage invasive breast cancer: a meta-analysis and systematic review. J Clin Oncol. 2004, 22 (19): 4010-4018.
Collins RF, Bekker HL, Dodwell DJ: Follow-up care of patients treated for breast cancer: a structured review. Cancer Treat Rev. 2004, 30 (19): 19-35.
Molino A: What is the best follow-up methodology in early breast cancer?. Breast. 2008, 17 (1): 1-2.
Leoni M, Sadacharan R, Louis D, Falcini F, Rabinowitz C, Cisbani L, De Palma R, Yuen E, Grilli R: Variation among local health units in follow-up care of breast cancer patients in Emilia-Romagna, Italy. Tumori. 2013, 99 (1): 30-34.
Grandjean I, Kwast AB, de Vries H, Klaase J, Schoevers WJ, Siesling S: Evaluation of the adherence to follow-up care guidelines for women with breast cancer. Eur J Oncol Nurs. 2012, 16 (3): 281-285.
Margenthaler JA, Allam E, Chen L, Virgo KS, Kulkarni UM, Patel AP, Johnson FE: Surveillance of patients with breast cancer after curative-intent primary treatment: current practice patterns. J Oncol Pract. 2012, 8 (2): 79-83.
Grunfeld E, Hodgson DC, Del Giudice ME, Moineddin R: Population-based longitudinal study of follow-up care for breast cancer survivors. J Oncol Pract. 2010, 6 (4): 174-181.
Zhou WB, Zhang PL, Liu XA, Yang T, He W: Innegligible musculoskeletal disorders caused by zoledronic acid in adjuvant breast cancertreatment: a meta-analysis. J Exp Clin Cancer Res. 2011, 30 (1): 72-78.
Sagawa Y, Armand S, Lubbeke A, Hoffmeyer P, Fritschy D, Suva D, Turcot K: Associations between gait and clinical parameters in patients with severe knee osteoarthritis: A multiple correspondence analysis. Clin Biomech (Bristol, Avon). 2013, 28 (3): 299-305.
Aihara T, Takatsuka Y, Ohsumi S, Aogi K, Hozumi Y, Imoto S, Mukai H, Iwata H, Watanabe T, Shimizu C, Nakagami K, Tamura M, Ito T, Masuda N, Ogino N, Hisamatsu K, Mitsuyama S, Abe H, Tanaka S, Yamaguchi T, Ohashi Y: Phase III randomized adjuvant study of tamoxifen alone versus sequential tamoxifen and anastrozole in Japanese postmenopausal women with hormone-responsive breast cancer: N-SAS BC03 study. Breast Cancer Res Treat. 2010, 121 (2): 379-387.
Amadori D, Silvestrini R, Lena M, Boccardo F, Rocca A, Scarpi E, Schittulli F, Brandi M, Maltoni R, Serra P, Ponzone R, Biglia N, Gianni L, Tienghi A, Valerio MR, Bonginelli P, Amaducci L, Faedi M, Baldini E, Paradiso A: Randomized phase III trial of adjuvant epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) versus CMF followed by epirubicin in patients with node-negative or 1–3 node-positive rapidly proliferating breast cancer. Breast Cancer Res Treat. 2011, 125 (3): 775-784.
Arriagada R, Spielmann M, Koscielny S, Le Chevalier T, Delozier T, Rémé-Saumon M, Ducourtieux M, Tursz T, Hill C: Results of two randomized trials evaluating adjuvant anthracycline-based chemotherapy in 1 146 patients with early breast cancer. Acta Oncol. 2005, 44 (5): 458-466.
Arriagada RLM, Spielmann M, Mauriac L, Bonneterre J, Namer M, Delozier T, Hill C, Tursz T: Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy. Ann Oncol. 2005, 16 (3): 389-396.
Bedognetti D, Sertoli MR, Pronzato P, Del Mastro L, Venturini M, Taveggia P, Zanardi E, Siffredi G, Pastorino S, Queirolo P, Gardin G, Wang E, Monzeglio C, Boccardo F, Bruzzi P: Concurrent vs Sequential Adjuvant Chemotherapy and Hormone Therapy in Breast Cancer: A Multicenter Randomized Phase III Trial. J Natl Cancer Inst. 2011, 103 (20): 1529-1539.
Boccardo FRA, Puntoni M, Guglielmini P, Amoroso D, Fini A, Paladini G, Mesiti M, Romeo D, Rinaldini M, Scali S, Porpiglia M, Benedetto C, Restuccia N, Buzzi F, Franchi R, Massidda B, Distante V, Amadori D, Sismondi P: Switching to Anastrozole Versus Continued Tamoxifen Treatment of Early Breast Cancer: Preliminary Results of the Italian Tamoxifen Anastrozole Trial. J Clin Oncol. 2005, 23 (22): 5138-5147.
Burnell M, Levine MN, Chapman JAW, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O’Brien P, Shepherd LE: Cyclophosphamide, Epirubicin, and Fluorouracil Versus Dose-Dense Epirubicin and Cyclophosphamide Followed by Paclitaxel Versus Doxorubicin and Cyclophosphamide Followed by Paclitaxel in Node-Positive or High-Risk Node-Negative Breast Cancer. J Clin Oncol. 2009, 28 (1): 77-82.
Coombes RC, Bliss JM, Espie M, Erdkamp F, Wals J, Tres A, Marty M, Coleman RE, Tubiana-Mathieu N, den Boer MO, Wardley A, Kilburn LS, Cooper D, Thomas MW, Reise JA, Wilkinson K, Hupperets P: Randomized, Phase III Trial of Sequential Epirubicin and Docetaxel Versus Epirubicin Alone in Postmenopausal Patients With Node-Positive Breast Cancer. J Clin Oncol. 2011, 29 (24): 3247-3254.
Coombes RC HE, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lonning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, Van De Velde C, Intergroup Exemestane Study: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004, 350 (11): 1081-1092.
Davidson NEONA, Vukov AM, Osborne CK, Martino S, White DR, Abeloff MD: Chemoendocrine Therapy for Premenopausal Women With Axillary Lymph Node-Positive, Steroid Hormone Receptor-Positive Breast Cancer: Results From INT 0101 (E5188). J Clin Oncol. 2005, 23 (25): 5973-5982.
De Placido S, De Laurentiis M, De Lena M, Lorusso V, Paradiso A, D’Aprile M, Pistillucci G, Farris A, Sarobba MG, Palazzo S, Manzione L, Adamo V, Palmeri S, Ferraù F, Lauria R, Pagliarulo C, Petrella G, Limite G, Costanzo R, Bianco AR, GOCSI Cooperative Group: A randomised factorial trial of sequential doxorubicin and CMF vs CMF and chemotherapy alone vs chemotherapy followed by goserelin plus tamoxifen as adjuvant treatment of node-positive breast cancer. Br J Cancer. 2005, 14 (3): 467-474.
Eiermann W, Graf E, Ataseven B, Conrad B, Hilfrich J, Massinger-Biebl H, Vescia S, Loibl S, von Minckwitz G, Schumacher M, Kaufmann M: Dose-intensified epirubicin versus standard-dose epirubicin/cyclophosphamide followed by CMF in breast cancer patients with 10 or more positive lymph nodes: Results of a randomised trial (GABG-IV E-93) – The German Adjuvant Breast Cancer Group. Eur J Cancer. 2010, 46 (1): 84-94.
Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martin M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press M, Sauter G, Lindsay MA, Riva A, Buyse M, Drevot P, Taupin H, Mackey JR: Phase III Study of Doxorubicin/Cyclophosphamide With Concomitant Versus Sequential Docetaxel As Adjuvant Treatment in Patients With Human Epidermal Growth Factor Receptor 2-Normal, Node-Positive Breast Cancer: BCIRG-005 Trial. J Clin Oncol. 2011, 29 (29): 3877-3884.
Ejlertsen B, Mouridsen HT, Jensen MB, Bengtsson NO, Bergh J, Cold S, Edlund P, Ewertz M, de Graaf PW, Kamby C, Nielsen DL: Similar Efficacy for Ovarian Ablation Compared With Cyclophosphamide, Methotrexate, and Fluorouracil: From a Randomized Comparison of Premenopausal Patients With Node-Positive, Hormone Receptor-Positive Breast Cancer. J Clin Oncol. 2006, 24 (31): 4956-4962.
Focan C, Beauduin M, Majois F, Canon JL, Cusumano G, Focan-Henrard D, Lobelle JP: High-dose oral medroxyprogesterone acetate or tamoxifen as adjuvant hormone therapy for node-negative early-stage breast cancer: randomized trial with 7-year update. Clin Breast Cancer. 2004, 5 (2): 136-141.
Fountzilas GSG, Kouvatseas G, Polychronis A, Klouvas G, Samantas E, Zamboglou N, Kyriakou K, Adamou A, Pectasidis D, Ekonomopoulos T, Kalofonos HP, Bafaloukos D, Georgoulias V, Razis E, Koukouras D, Zombolas V, Kosmidis P, Skarlos D, Pavlidis N, Hellenic Cooperative Oncology Group: Adjuvant cytotoxic and endocrine therapy in pre- and postmenopausal patients with breast cancer and one to nine infiltrated nodes: five-year results of the Hellenic Cooperative Oncology Group randomized HE 10/92 study. Am J Clin Oncol. 2004, 27 (1): 57-67.
Fumoleau P, Kerbrat P, Romestaing P, Fargeot P, Brémond A, Namer M, Schraub S, Goudier MJ, Mihura J, Monnier A, Clavère P, Serin D, Seffert P, Pourny C, Facchini T, Jacquin JP, Sztermer JF, Datchary J, Ramos R, Luporsi E: Randomized Trial Comparing Six Versus Three Cycles of Epirubicin-Based Adjuvant Chemotherapy in Premenopausal, Node-Positive Breast Cancer Patients: 10-Year Follow-Up Results of the French Adjuvant Study Group 01 Trial. J Clin Oncol. 2003, 21 (2): 298-305.
Gogas H, Dafni U, Karina M, Papadimitriou C, Batistatou A, Bobos M, Kalofonos HP, Eleftheraki AG, Timotheadou E, Bafaloukos D, Christodoulou C, Markopoulos C, Briasoulis E, Papakostas P, Samantas E, Kosmidis P, Stathopoulos GP, Karanikiotis C, Pectasides D, Dimopoulos MA, Fountzilas G: Postoperative dose-dense sequential versus concomitant administration of epirubicin and paclitaxel in patients with node-positive breast cancer: 5-year results of the Hellenic Cooperative Oncology Group HE 10/00 phase III Trial. Breast Cancer Res Treat. 2012, 132 (2): 609-619.
Goldstein LJ, O’Neill A, Sparano JA, Perez EA, Shulman LN, Martino S, Davidson NE: Concurrent Doxorubicin Plus Docetaxel Is Not More Effective Than Concurrent Doxorubicin Plus Cyclophosphamide in Operable Breast Cancer With 0 to 3 Positive Axillary Nodes: North American Breast Cancer Intergroup Trial E 2197. J Clin Oncol. 2008, 26 (25): 4092-4099.
Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E, Schilsky RL, Wood WC, Muss HB, Norton L: Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003, 21 (6): 976-983.
Ingle JN, Suman VJ, Mailliard JA, Kugler JW, Krook JE, Michalak JC, Pisansky TM, Wold LE, Donohue JH, Goetz MP, Perez EA: Randomized trial of tamoxifen alone or combined with fluoxymesterone as adjuvant therapy in postmenopausal women with resected estrogen receptor positive breast cancer. North Central Cancer Treatment Group Trial 89-30-52. Breast Cancer Res Treat. 2006, 98 (2): 217-222.
International Breast Cancer Study Group (IBCSG): Endocrine responsiveness and tailoring adjuvant therapy for postmenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst. 2002, 94 (14): 1054-1065.
Castiglione Gertsch M, O’Neill A, Price KN, Goldhirsch A, Coates AS, Colleoni M, Nasi ML, Bonetti M, Gelber RD, International Breast Cancer Study Group (IBCSG): Adjuvant Chemotherapy Followed by Goserelin Versus Either Modality Alone for Premenopausal Lymph Node-Negative Breast Cancer: A Randomized Trial. J Natl Cancer Inst. 2003, 95 (24): 1833-1846.
International Breast Cancer Study Group PO: Toremifene and tamoxifen are equally effective for early-stage breast cancer: first results of International Breast Cancer Study Group Trials 12–93 and 14–93. Ann Oncol. 2004, 15 (12): 1749-1759.
Gelber S, Goldhirsch A, Aebi S, Castiglione Gertsch M, Price KN, Coates AS, Gelber RD, International Breast Cancer Study Group CM: Tamoxifen After Adjuvant Chemotherapy for Premenopausal Women With Lymph Node-Positive Breast Cancer: International Breast Cancer Study Group Trial 13–93. J Clin Oncol. 2006, 24 (9): 1332-1341.
Basser RL, O’Neill A, Martinelli G, Green MD, Peccatori F, Cinieri S, Coates AS, Gelber RD, Aebi S, Castiglione-Gertsch M, Viale G, Price KN, Goldhirsch A: 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 (3): 370-378.
Jakesz R, Hausmaninger H, Kubista E, Gnant M, Menzel C, Bauernhofer T, Seifert M, Haider K, Mlineritsch B, Steindorfer P, Kwasny W, Fridrik M, Steger G, Wette V, Samonigg H, Austrian Breast and Colorectal Cancer Study Group Trial 5: Randomized Adjuvant Trial of Tamoxifen and Goserelin Versus Cyclophosphamide, Methotrexate, and Fluorouracil: Evidence for the Superiority of Treatment With Endocrine Blockade in Premenopausal Patients With Hormone-Responsive Breast Cancer--Austrian Breast and Colorectal Cancer Study Group Trial 5. J Clin Oncol. 2002, 20 (24): 4621-4627.
Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, Hilfrich J, Kwasny W, Menzel C, Samonigg H, Seifert M, Gademann G, Kaufmann M, Wolfgang J, ABCSG and the GABG: Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005, 366 (9484): 455-462.
Jones SE, Savin MA, Holmes FA, O’Shaughnessy JA, Blum JL, Vukelja S, McIntyre KJ, Pippen JE, Bordelon JH, Kirby R, Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards DA, Anthony SP, Mennel RG, Boehm KA, Meyer WG, Asmar L: Phase III Trial Comparing Doxorubicin Plus Cyclophosphamide With Docetaxel Plus Cyclophosphamide As Adjuvant Therapy for Operable Breast Cancer. J Clin Oncol. 2006, 24 (34): 5381-5387.
Kaufmann M, Graf E, Jonat W, Eiermann W, Vescia S, Geberth M, Conrad B, Gademann G, Albert U-S, Loibl S, von Minckwitz G, Schumacher M, German Adjuvant Breast Cancer Study Group (GABG): A randomised trial of goserelin versus control after adjuvant, risk-adapted chemotherapy in premenopausal patients with primary breast cancer – GABG-IV B-93. Eur J Cancer. 2007, 43 (16): 2351-2358.
Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I, von Minckwitz G: Improved Overall Survival in Postmenopausal Women With Early Breast Cancer After Anastrozole Initiated After Treatment With Tamoxifen Compared With Continued Tamoxifen: The ARNO 95 Study. J Clin Oncol. 2007, 25 (19): 2664-2670.
Kaufmann MGE, Jonat W, Eiermann W, Geberth M, Albert US, Gademann G, Conrad B, Stahl K, von Minckwitz G, Schumacher M, German Adjuvant Breast Cancer Group: Tamoxifen Versus Control After Adjuvant, Risk-Adapted Chemotherapy in Postmenopausal, Receptor-Negative Patients With Breast Cancer: A Randomized Trial (GABG-IV D-93)--The German Adjuvant Breast Cancer Grou. J Clin Oncol. 2005, 23 (31): 7842-7848.
Kimura M, Tominaga T, Takatsuka Y, Toi M, Abe R, Koyama H, Takashima S, Nomura Y, Miura S, Kimijima I, Tashiro H, Ohashi Y, Adjuvant CEF Research Group for Breast Cancer: Randomized trial of cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil with node-positive breast cancer in Japan. Breast Cancer. 2010, 17 (3): 190-198.
Lewis JD, Chagpar AB, Shaughnessy EA, Nurko J, McMasters K, Edwards MJ: Excellent outcomes with adjuvant toremifene or tamoxifen in early stage breast cancer. Cancer. 2010, 116 (10): 2307-2315.
Loesch D, Greco FA, Senzer NN, Burris HA, Hainsworth JD, Jones S, Vukelja SJ, Sandbach J, Holmes F, Sedlacek S, Pippen J, Lindquist D, McIntyre K, Blum JL, Modiano MR, Boehm KA, Zhan F, Asmar L, Robert N: Phase III Multicenter Trial of Doxorubicin Plus Cyclophosphamide Followed by Paclitaxel Compared With Doxorubicin Plus Paclitaxel Followed by Weekly Paclitaxel As Adjuvant Therapy for Women With High-Risk Breast Cancer. J Clin Oncol. 2010, 28 (18): 2958-2965.
Love RR, Duc NB, Allred DC, Binh NC, Dinh NV, Kha NN, Thuan TV, Mohsin SK, le Roanh D, Khang HX, Tran TL, Quy TT, Thuy NV, Thé PN, Cau TT, Tung ND, Huong DT, le Quang M, Hien NN, Thuong L, Shen TZ, Xin Y, Zhang Q, Havighurst TC, Yang YF, Hillner BE, DeMets DL: Oophorectomy and Tamoxifen Adjuvant Therapy in Premenopausal Vietnamese and Chinese Women With Operable Breast Cancer. J Clin Oncol. 2002, 20 (10): 2559-2566.
Mamounas EPBJ, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N: Paclitaxel After Doxorubicin Plus Cyclophosphamide As Adjuvant Chemotherapy for Node-Positive Breast Cancer: Results From NSABP B-28. J Clin Oncol. 2005, 23 (16): 3686-3696.
Martin M, Segui MA, Anton A, Ruiz A, Ramos M, Adrover E, Aranda I, Rodriguez Lescure A, Grosse R, Calvo L, Barnadas A, Isla D, Martinez Del Prado P, Ruiz Borrego M, Zaluski J, Arcusa A, Muñoz M, Lopez Vega JM, Mel JR, Munarriz B, Llorca C, Jara C, Alba E, Florian J, Li J, Lopez Garcia Asenjo JA, Saez A, Rios MJ, Almenar S, Peiro G, Lluch A, GEICAM 9805 Investigators: Adjuvant Docetaxel for High-Risk, Node-Negative Breast Cancer. N Engl J Med. 2010, 363 (23): 2200-2210.
Martin M, Rodriguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munarriz B, Rodriguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM, GEICAM 9906 Study Investigators: Randomized Phase 3 Trial of Fluorouracil, Epirubicin, and Cyclophosphamide Alone or Followed by Paclitaxel for Early Breast Cancer. J Natl Cancer Inst. 2008, 100 (11): 805-814.
Martin MPT, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C, Breast Cancer International Research Group 001 Investigators: Adjuvant Docetaxel for Node-Positive Breast Cancer. N Engl J Med. 2005, 352 (22): 2302-2313.
Nitz UA, Mohrmann S, Fischer J, Lindemann W, Berdel WE, Jackisch C, Werner C, Ziske C, Kirchner H, Metzner B: 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 (9501): 1935-1944.
Park Y, Okamura K, Mitsuyama S, Saito T, Koh J, Kyono S, Higaki K, Ogita M, Asaga T, Inaji H, Komichi H, Kohno N, Yamazaki K, Tanaka F, Ito T, Nishikawa H, Osaki A, Koyama H, Suzuki T: Uracil-tegafur and tamoxifen vs cyclophosphamide, methotrexate, fluorouracil, and tamoxifen in post-operative adjuvant therapy for stage I, II, or IIIA lymph node-positive breast cancer: a comparative study. Br J Cancer. 2009, 101 (4): 598-604.
Paterson AH, Anderson SJ, Lembersky BC, Fehrenbacher L, Falkson CI, King KM, Weir LM, Brufsky AM, Dakhil S, Lad T, Baez-Diaz L, Gralow JR, Robidoux A, Perez EA, Zheng P, Geyer CE, Swain SM, Costantino JP, Mamounas EP, Wolmark N: Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial. Lancet Oncol. 2012, 13 (7): 734-742.
Piccart-Gebhart MJPM, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD, Herceptin Adjuvant (HERA) Trial Study Team: Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer. N Engl J Med. 2005, 335 (16): 1659-1672.
Ploner F, Jakesz R, Hausmaninger H, Kolb R, Stierer M, Fridrik M, Steindorfer P, Gnant M, Haider K, Mlineritsch B, Tschurtschenthaler G, Steger G, Seifert M, Kubista E, Samonigg H, Austrian Breast And Colorectal Cancer Study Group: Randomised trial: One cycle of anthracycline-containing adjuvant chemotherapy compared with six cycles of CMF treatment in node-positive, hormone receptor-negative breast cancer patients. Onkologie. 2003, 26 (2): 115-119.
Polyzos A, Malamos N, Boukovinas I, Adamou A, Ziras N, Kalbakis K, Kakolyris S, Syrigos K, Papakotoulas P, Kouroussis C, Karvounis N, Vamvakas L, Christophyllakis C, Athanasiadis A, Varthalitis I, Georgoulias V, Mavroudis D: FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG). Breast Cancer Res Treat. 2010, 119 (1): 95-104.
Pritchard KI, Shepherd LE, Chapman JA, Norris BD, Cantin J, Goss PE, Dent SF, Walde D, Vandenberg TA, Findlay B, O’Reilly SE, Wilson CF, Han L, Piura E, Whelan TJ, Pollak MN: Randomized trial of tamoxifen versus combined tamoxifen and octreotide LAR Therapy in the adjuvant treatment of early-stage breast cancer in postmenopausal women: NCIC CTG MA. 14. J Clin Oncol. 2011, 29 (29): 3869-3876.
Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B: Sequential Adjuvant Epirubicin-Based and Docetaxel Chemotherapy for Node-Positive Breast Cancer Patients: The FNCLCC PACS 01 Trial. J Clin Oncol. 2006, 24 (36): 5664-5671.
Rodenhuis S, Bontenbal M, Beex LV, Wagstaff J, Richel DJ, Nooij MA, Voest EE, Hupperets P, Van Tinteren H, Peterse HL, TenVergert EM, De Vries EG: Netherlands Working Party on Autologous Transplantation in Solid Tumors: High-Dose Chemotherapy with Hematopoietic Stem-Cell Rescue for High-Risk Breast Cancer. N Engl J Med. 2003, 349 (1): 7-16.
Rydén L, Jönsson P-E, Chebil G, Dufmats M, Fernö M, Jirström K, Källström A-C, Landberg G, Stål O, Thorstenson S, Nordenskjöld B: Two years of adjuvant tamoxifen in premenopausal patients with breast cancer: a randomised, controlled trial with long-term follow-up. Eur J Cancer. 2005, 41 (2): 256-264.
Sacco MVM, Belfiglio M, Pellegrini F, De Berardis G, Franciosi M, Nicolucci A, Italian Interdisciplinary Group for Cancer Care Evaluation: Randomized Trial of 2 Versus 5 Years of Adjuvant Tamoxifen for Women Aged 50 Years or Older With Early Breast Cancer: Italian Interdisciplinary Group for Cancer Evaluation Study of Adjuvant Treatment in Breast Cancer 01. J Clin Oncol. 2003, 21 (12): 2276-2281.
Schmid MJR, Samonigg H, Kubista E, Gnant M, Menzel C, Seifert M, Haider K, Taucher S, Mlineritsch B, Steindorfer P, Kwasny W, Stierer M, Tausch C, Fridrik M, Wette V, Steger G, Hausmaninger H: Randomized Trial of Tamoxifen Versus Tamoxifen Plus Aminoglutethimide as Adjuvant Treatment in Postmenopausal Breast Cancer Patients With Hormone Receptor-Positive Disease: Austrian Breast and Colorectal Cancer Study Group Trial 6. J Clin Oncol. 2003, 21 (6): 984-990.
Schmid P, Untch M, Kosse V, Bondar G, Vassiljev L, Tarutinov V, Lehmann U, Maubach L, Meurer J, Wallwiener D, Possinger K: Leuprorelin Acetate Every-3-Months Depot Versus Cyclophosphamide, Methotrexate, and Fluorouracil As Adjuvant Treatment in Premenopausal Patients With Node-Positive Breast Cancer: The TABLE Study. J Clin Oncol. 2007, 25 (18): 2509-2515.
Schmid P, Untch M, Wallwiener D, Kosse V, Bondar G, Vassiljev L, Tarutinov V, Kienle E, Luftner D, Possinger K, TABLE-study (Takeda Adjuvant Breast cancer study with Leuprorelin Acetate): Cyclophosphamide, methotrexate and fluorouracil (CMF) versus hormonal ablation with leuprorelin acetate as adjuvant treatment of node-positive, premenopausal breast cancer patients: preliminary results of the TABLE-study (Takeda Adjuvant Breast cancer study with Leuprorelin Acetate). Anticancer Res. 2002, 22 (4): 2325-2332.
Spielmann M, Roche H, Delozier T, Canon JL, Romieu G, Bourgeois H, Extra JM, Serin D, Kerbrat P, Machiels JP, Lortholary A, Orfeuvre H, Campone M, Hardy-Bessard AC, Coudert B, Maerevoet M, Piot G, Kramar A, Martin AL, Penault-Llorca F: Trastuzumab for Patients With Axillary-Node-Positive Breast Cancer: Results of the FNCLCC-PACS 04 Trial. J Clin Oncol. 2009, 27 (36): 6129-6134.
Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, Sahmoud T, ATAC Trialists’ Group: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002, 359 (9324): 2131-2139.
Thurlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A: A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005, 353 (26): 2747-2757.
Tokuda Y, Tajima T, Narabayashi M, Takeyama K, Watanabe T, Fukutomi T, Chou T, Sano M, Igarashi T, Sasaki Y, Ogura M, Miura S, Okamoto S, Ogita M, Kasai M, Kobayashi T, Fukuda H, Takashima S, Tobinai K, Autologous Bone Marrow Transplantation Study Group;Breast Cancer Study Group of the Japan Clinical Oncology Group (JCOG): Phase III study to evaluate the use of high-dose chemotherapy as consolidation of treatment for high-risk postoperative breast cancer: Japan Clinical Oncology Group study, JCOG 9208. Cancer Sci. 2008, 99 (1): 145-51.
Venturini M, Del Mastro L, Aitini E, Baldini E, Caroti C, Contu A, Testore F, Brema F, Pronzato P, Cavazzini G, Sertoli MR, Canavese G, Rosso R, Bruzzi P: Dose-Dense Adjuvant Chemotherapy in Early Breast Cancer Patients: Results From a Randomized Trial. J Natl Cancer Inst. 2005, 97 (23): 1724-1733.
Vici P, Brandi M, Giotta F, Foggi P, Schittulli F, Di Lauro L, Gebbia N, Massidda B, Filippelli G, Giannarelli D, Di Benedetto A, Mottolese M, Colucci G, Lopez M: A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer. GOIM (Gruppo Oncologico Italia Meridionale) 9902 study. Ann Oncol. 2012, 23 (5): 1121-1129.
von Minckwitz G, Graf E, Geberth M, Eiermann W, Jonat W, Conrad B, Brunnert K, Gerber B, Vescia S, Wollert J, Kaufmann M: CMF versus goserelin as adjuvant therapy for node-negative, hormone-receptor-positive breast cancer in premenopausal patients: A randomised trial (GABG trial IV-A-93). Eur J Cancer. 2006, 42 (12): 1780-1788.
Winzer KJ, Sauer R, Sauerbrei W, Schneller E, Jaeger W, Braun M, Dunst J, Liersch T, Zedelius M, Brunnert K, Guski H, Schmoor C, Schumacher M, German Breast Cancer Study Group: Radiation therapy after breast-conserving surgery. Eur J Cancer. 2004, 40 (7): 998-1005.
Zander ARKN, Schmoor C, Krüger W, Möbus V, Frickhofen N, Metzner B, Schultze W, Berdel WE, Koenigsmann M, Thiel E, Wandt H, Possinger K, Trümper L, Kreienberg R, Carstensen M, Schmidt EH, Jänicke F, Schumacher M, Jonat W: High-Dose Chemotherapy With Autologous Hematopoietic Stem-Cell Support Compared With Standard-Dose Chemotherapy in Breast Cancer Patients With 10 or More Positive Lymph Nodes: First Results of a Randomized Trial. J Clin Oncol. 2004, 22 (12): 2273-2283.
van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, Paridaens R, Markopoulos C, Hozumi Y, Hille ET, Kieback DG, Asmar L, Smeets J, Nortier JW, Hadji P, Bartlett JM, Jones SE: Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet. 2011, 377 (9762): 321-331.
Kerbrat P, Roché H, Bonneterre J, Veyret C, Lortholary A, Monnier A, Fumoleau P, Fargeot P, Namer M, Chollet P, Goudier MJ, Audhuy B, Simon H, Montcuquet P, Eymard JC, Walter S, Clavère P, Guastalla JP, French adjuvant Study Group: Epirubicin–vinorelbine vs FEC100 for node-positive, early breast cancer: French Adjuvant Study Group 09 trial. Br J Cancer. 2007, 96 (11): 1633-1638.
Albain KS, Barlow WE, Ravdin PM, Farrar WB, Burton GV, Ketchel SJ, Cobau CD, Levine EG, Ingle JN, Pritchard KI, Lichter AS, Schneider DJ, Abeloff MD, Henderson IC, Muss HB, Green SJ, Lew D, Livingston RB, Martino S, Osborne CK, Breast Cancer Intergroup of North America: Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009, 374 (9707): 2055-2063.
Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003, 21 (8): 1431-1439.
Coleman RE, Marshall H, Cameron D, Dodwell D, Burkinshaw R, Keane M, Gil M, Houston SJ, Grieve RJ, Barrett-Lee PJ, Ritchie D, Pugh J, Gaunt C, Rea U, Peterson J, Davies C, Hiley V, Gregory W, Bell R, AZURE Investigators: Breast-cancer adjuvant therapy with zoledronic acid. N Engl J Med. 2011, 365 (15): 1396-1405.
Dubsky PC, Jakesz R, Mlineritsch B, Postlberger S, Samonigg H, Kwasny W, Tausch C, Stoger H, Haider K, Fitzal F, Singer CF, Stierer M, Sevelda P, Luschin-Ebengreuth G, Taucher S, Rudas M, Bartsch R, Steger GG, Greil R, Filipcic L, Gnant M: Tamoxifen and Anastrozole As a Sequencing Strategy: A Randomized Controlled Trial in Postmenopausal Patients With Endocrine-Responsive Early Breast Cancer From the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 2012, 30 (7): 722-728.
Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O’Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM, TACT Trial Management Group: TACT Trialists: Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet Oncol. 2009, 373 (9676): 1681-1692.
Francis P, Crown J, Di Leo A, Buyse M, Balil A, Andersson M, Nordenskjold B, Lang I, Jakesz R, Vorobiof D, Gutiérrez J, van Hazel G, Dolci S, Jamin S, Bendahmane B, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, Piccart-Gebhart M, BIG 02–98 Collaborative Group: Adjuvant Chemotherapy With Sequential or Concurrent Anthracycline and Docetaxel: Breast International Group 02 98 Randomized Trial. J Natl Cancer Inst. 2008, 100 (2): 121-133.
Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Postlberger S, Menzel C, Jakesz R, Seifert M, Hubalek M, Bjelic-Radisic V, Samonigg H, Tausch C, Eidtmann H, Steger G, Kwasny W, Dubsky P, Fridrik M, Fitzal F, Stierer M, Rücklinger E, Greil R, ABCSG-12 Trial Investigators, Marth C: Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009, 360 (7): 679-691.
Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL: A Randomized Trial of Letrozole in Postmenopausal Women after Five Years of Tamoxifen Therapy for Early-Stage Breast Cancer. N Engl J Med. 2003, 349 (19): 1793-1802.
Hughes KSSL, Berry D, Cirrincione C, McCormick B, Shank B, Wheeler J, Champion LA, Smith TJ, Smith BL, Shapiro C, Muss HB, Winer E, Hudis C, Wood W, Sugarbaker D, Henderson IC, Norton L, Cancer and Leukemia Group B; Radiation Therapy Oncology Group; Eastern Cooperative Oncology Group: Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer. N Engl J Med. 2004, 351 (10): 971-977.
Hutchins LFGS, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK: Randomized, Controlled Trial of Cyclophosphamide, Methotrexate, and Fluorouracil Versus Cyclophosphamide, Doxorubicin, and Fluorouracil With and Without Tamoxifen for High-Risk, Node-Negative Breast Cancer: Treatment Results of Intergroup Protocol INT-0102. J Clin Oncol. 2005, 23: 8313-8321.
Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Asola R, Kokko R, Ahlgren J, Auvinen P, Hemminki A, Paija O, Helle L, Nuortio L, Villman K, Nilsson G, Lahtela SL, Lehtiö K, Pajunen M, Poikonen P, Nyandoto P, Kataja V, Bono P, Leinonen M, Lindman H, FinXX Study Investigators: Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial. Lancet Oncol. 2009, 10 (12): 1145-1151.
Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J, FinHer Study Investigators: Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006, 354 (8): 809-820.
Leonard RCF, Lind M, Twelves C, Coleman R, van Belle S, Wilson C, Ledermann J, Kennedy I, Barrett-Lee P, Perren T, Verrill M, Cameron D, Foster E, Yellowlees A, Crown J, Anglo-Celtic Cooperative Oncology Group: Conventional Adjuvant Chemotherapy Versus Single-Cycle, Autograft-Supported, High-Dose, Late-Intensification Chemotherapy in High-Risk Breast Cancer Patients: A Randomized Trial. J Natl Cancer Inst. 2004, 96 (14): 1076-1083.
Moebus V, Jackisch C, Lueck HJ, du Bois A, Thomssen C, Kurbacher C, Kuhn W, Nitz U, Schneeweiss A, Huober J, Harbeck N, von Minckwitz G, Runnebaum IB, Hinke A, Kreienberg R, Konecny GE, Untch M: Intense Dose-Dense Sequential Chemotherapy With Epirubicin, Paclitaxel, and Cyclophosphamide Compared With Conventionally Scheduled Chemotherapy in High-Risk Primary Breast Cancer: Mature Results of an AGO Phase III Study. J Clin Oncol. 2010, 28 (17): 2874-2880.
Moore HCF, Green SJ, Gralow JR, Bearman SI, Lew D, Barlow WE, Hudis C, Wolff AC, Ingle JN, Chew HK, Elias AD, Livingston RB, Martino S, Southwest Oncology Group/Intergroup Study 9623: Intensive Dose-Dense Compared With High-Dose Adjuvant Chemotherapy for High-Risk Operable Breast Cancer: Southwest Oncology Group/Intergroup Study 9623. J Clin Oncol. 2007, 25 (13): 1677-1682.
Petit T, Borel C, Theobald S, Serin D, Rodier JF, Prevot G, Brettes JP, Klein T: Randomized multicentric study of perioperative chemotherapy with mitoxantrone in early breast cancer. Ann Surg Oncol. 2003, 10 (4): 369-375.
Pico CMM, Jara C, Barnadas A, Pelegri A, Balil A, Camps C, Frau A, Rodriguez-Lescure A, Lopez-Vega JM, De La Haba J, Tres A, Alvarez I, Alba E, Arcusa A, Oltra A, Batista N, Checa T, Perez-Carrion R, Curto J, GEICAM Group: Epirubicin-cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: randomized phase III trial in postmenopausal node-positive breast cancer patients. A GEICAM 9401 study. Ann Oncol. 2004, 15 (1): 79-87.
Poole CJEH, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O’Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ, NEAT Investigators and the SCTBG: Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006, 355 (18): 1851-1862.
Rao RD, Cobleigh MA, Gray R, Graham ML, Norton L, Martino S, Budd GT, Ingle JN, Wood WC: Phase III double-blind, placebo-controlled, prospective randomized trial of adjuvant tamoxifen vs. tamoxifen and fenretinide in postmenopausal women with positive receptors (EB193): an intergroup trial coordinated by the Eastern Cooperative Oncology Group. Med Oncol. 2011, 1 (28): S39-47.
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N: Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer. N Engl J Med. 2005, 353 (16): 1673-1684.
Sawaki M, Tokudome N, Mizuno T, Nakayama T, Taira N, Bando H, Murakami S, Yamamoto Y, Kashiwaba M, Iwata H, Uemura Y, Ohashi Y: Evaluation of trastuzumab without chemotherapy as a post-operative adjuvant therapy in HER2-positive elderly breast cancer patients: randomized controlled trial [RESPECT (N-SAS BC07)]. Jpn J Clin Oncol. 2011, 41 (5): 709-712.
Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O’Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C: Six cycles of doxorubicin and cyclophosphamide or Paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012, 30 (33): 4071-4076.
Sparano JAWM, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW, Wood WC, Davidson NE: Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008, 358 (16): 1663-1671.
Tallman MSRG, Robert NJ, LeMaistre CF, Osborne CK, Vaughan WP, Gradishar WJ, Pisansky TM, Fetting J, Paietta E, Lazarus HM: Conventional Adjuvant Chemotherapy with or without High-Dose Chemotherapy and Autologous Stem-Cell Transplantation in High-Risk Breast Cancer. N Engl J Med. 2003, 349 (1): 17-26.
Tominaga T, Toi M, Abe O, Ohashi Y, Uchino J, Hayasaka H, Abe R, Izuo M, Enomoto K, Watanabe H, Yoshida M, Taguchi T, Koyama H, Senoo T, Toge T, Monden Y, Hattori T, Nomura Y, Sugimachi K, Hirata K, Nakazato H, Miura S, Morimoto T, Asaishi K, Kimijima I, Ota J, Sonoo H, Yamaguchi S, 5′-BC Study Group (5′-DFUR Adjuvant Chemotherapy for Breast Cancer Study Group): The effect of adjuvant 5′-deoxy-5-fluorouridine in early stage breast cancer patients: results from a multicenter randomized controlled trial. Int J Oncol. 2002, 20 (3): 517-525.
Watanabe T, Sano M, Takashima S, Kitaya T, Tokuda Y, Yoshimoto M, Kohno N, Nakagami K, Iwata H, Shimozuma K, Sonoo H, Tsuda H, Sakamoto G, Ohashi Y: Oral Uracil and Tegafur Compared With Classic Cyclophosphamide, Methotrexate, Fluorouracil As Postoperative Chemotherapy in Patients With Node-Negative, High-Risk Breast Cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial. J Clin Oncol. 2009, 27 (9): 1368-1374.
Sirohi B, A’Hern R, Coombes G, Bliss JM, Hickish T, Perren T, Crawford M, O’Brien M, Iveson T, Ebbs S, Skene A, Laing R, Smith IE: A randomised comparative trial of infusional ECisF versus conventional FEC as adjuvant chemotherapy in early breast cancer: the TRAFIC trial. Ann Oncol. 2010, 21 (8): 1623-1629.
Tada K, Yoshimoto M, Nishimura S, Takahashi K, Makita M, Iwase T, Takahashi S, Ito Y, Hatake K, Ueno M, Nakagawa K, Kasumi F: Comparison of two-year and five-year tamoxifen use in Japanese post-menopausal women. Eur J Surg Oncol. 2004, 30 (10): 1077-1083.
Adjuvant Breast Cancer Trials Collaborative Group: Polychemotherapy for early breast cancer: results from the international adjuvant breast cancer chemotherapy randomized trial. J Natl Cancer Inst. 2007, 99 (7): 506-515.
Adjuvant Breast Cancer Trials Collaborative Group: Ovarian ablation or suppression in premenopausal early breast cancer: results from the international adjuvant breast cancer ovarian ablation or suppression randomized trial. J Natl Cancer Inst. 2007, 99 (7): 516-525.
Martin M, Villar A, Sole-Calvo A, Gonzalez R, Massuti B, Lizon J, Camps C, Carrato A, Casado A, Candel MT, Albanell J, Aranda J, Munarriz B, Campbell J, Diaz-Rubio E, GEICAM Group (Spanish Breast Cancer Research Group), Spain: Doxorubicin in combination with fluorouracil and cyclophosphamide (i.v. FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (i.v. CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Ann Oncol. 2003, 14 (6): 833-842.
Linden HM, Haskell CM, Green SJ, Osborne CK, Sledge GW, Shapiro CL, Ingle JN, Lew D, Hutchins LF, Livingston RB, Martino S: Sequenced Compared With Simultaneous Anthracycline and Cyclophosphamide in High-Risk Stage I and II Breast Cancer: Final Analysis From INT-0137 (S9313). J Clin Oncol. 2007, 25 (6): 656-661.
Recommended breast cancer surveillance guidelines: American Society of Clinical Oncology. J Clin Oncol. 1997, 15 (5): 2149-2156.
Oltra A, Santaballa A, Munarriz B, Pastor M, Montalar J: Cost-benefit analysis of a follow-up program in patients with breast cancer: a randomized prospective study. Breast J. 2007, 13 (6): 571-574.
van Hezewijk M, van den Akker ME, van de Velde CJ, Scholten AN, Hille ET: Costs of different follow-up strategies in early breast cancer: a review of the literature. Breast. 2012, 21 (6): 693-700.
Kokko R, Hakama M, Holli K: Follow-up cost of breast cancer patients with localized disease after primary treatment: a randomized trial. Breast Cancer Res Treat. 2005, 93 (3): 255-260.
Pagani O, Senkus E, Wood W, Colleoni M, Cufer T, Kyriakides S, Costa A, Winer EP, Cardoso F: International Guidelines for Management of Metastatic Breast Cancer: Can Metastatic Breast Cancer Be Cured?. J Natl Cancer Inst. 2010, 102 (7): 456-463.
Ogawa Y, Ikeda K, Izumi T, Okuma S, Ichiki M, Ikeya T, Morimoto J, Nishiguchi Y, Ikehara T: First indicators of relapse in breast cancer: evaluation of the follow-up program at our hospital. Int J Clin Oncol. 2012, 18 (3): 447-53.
Barni S, Venturini M, Molino A, Donadio M, Rizzoli S, Maiello E, Gori S: Importance of adherence to guidelines in breast cancer clinical practice. The Italian experience (AIOM). Tumori. 2011, 97 (5): 559-563.
Donnelly P, Hiller L, Bathers S, Bowden S, Coleman R: Questioning specialists’ attitudes to breast cancer follow-up in primary care. Ann Oncol. 2007, 18 (9): 1467-1476.
Montgomery DA, Krupa K, Cooke TG: Alternative methods of follow up in breast cancer: a systematic review of the literature. Br J Cancer. 2007, 96 (11): 1625-1632.
Geurts SM, De Vegt F, Siesling S, Flobbe K, Aben KK, Van Der Heiden Van Der Loo M, Verbeek AL, Van Dijck JA, Tjan Heijnen VC: Pattern of follow-up care and early relapse detection in breast cancer patients. Breast Cancer Res Treat. 2012, 136 (3): 859-868.
Dewar JA, Kerr GR: Value of routine follow up of women treated for early carcinoma of the breast. Br Med J (Clin Res Ed). 1985, 291 (6507): 1464-1467.
Pandya KJ, McFadden ET, Kalish LA, Tormey DC, Taylor SG, Falkson G: A retrospective study of earliest indicators of recurrence in patients on Eastern Cooperative Oncology Group adjuvant chemotherapy trials for breast cancer. A preliminary report. Cancer. 1985, 55 (1): 202-205.
Schapira DV, Urban N: A minimalist policy for breast cancer surveillance. JAMA. 1991, 265 (3): 380-382.
Zwaveling A, Albers GH, Felthuis W, Hermans J: An evaluation of routine follow-up for detection of breast cancer recurrences. J Surg Oncol. 1987, 34 (3): 194-197.
Smith TJ, Davidson NE, Schapira DV, Grunfeld E, Muss HB, Vogel VG, Somerfield MR: American Society of Clinical Oncology 1998 update of recommended breast cancer surveillance guidelines. J Clin Oncol. 1999, 17 (3): 1080-1082.
Bonomi M, Pilotto S, Milella M, Massari F, Cingarlini S, Brunelli M, Chilosi M, Tortora G, Bria E: Adjuvant chemotherapy for resected non-small-cell lung cancer: future perspectives for clinical research. J Exp Clin Cancer Res. 2011, 30 (1): 115-123.
Supported by the Consorzio Interuniversitario Nazionale per Bio-Oncologia (CINBO). The authors are grateful to Mrs. Camille St. Pierre for careful reviewing of the manuscript.
The authors have no potential conflicts of interest to declare.
IS supervised the data collection, performed the statistical analyses and revised the manuscript; AG, MDT and GC performed literature search and data extraction; NT and TG wrote the manuscript; PV and SI critically revised the manuscript; CN conceived the study and critically revised the manuscript. All authors read and approved the final manuscript.
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Sperduti, I., Vici, P., Tinari, N. et al. Breast cancer follow-up strategies in randomized phase III adjuvant clinical trials: a systematic review. J Exp Clin Cancer Res 32, 89 (2013) doi:10.1186/1756-9966-32-89
- Breast cancer
- Phase III clinical trial
- Systematic review