|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 4 (February 1), 2007: pp. 405-410 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.8576 Phase III Trial of Concurrent or Sequential Adjuvant Chemoradiotherapy After Conservative Surgery for Early-Stage Breast Cancer: Final Results of the ARCOSEIN Trial
From the Department of Radiation Oncology, Henry Kaplan, Hôpital Bretonneau, Tours; Centre Régional de Lutte Contre le Cancer Val d'Aurelle, Montpellier; Institut Sainte-Catherine, Avignon; Institut Curie, Paris; Hôpital Minjoz, Besançon; and Hôpital La Source, Orléans; France Address reprint requests to Alain Toledano, MD, Department of Radiation Oncology, Henry Kaplan, Hôpital Bretonneau, 2 Bd Tonnellé, 37044 Tours Cedex 9, France; e-mail: alain.toledano{at}gmail.com
Purpose In 1996, we initiated the French multicenter phase III randomized trial to compare the effect on disease-free survival (DFS) of concurrent versus sequential chemotherapy (CT) and radiotherapy (RT) after breast-conserving surgery for stages I and II breast cancer. This report presents the clinical results with a median follow-up of 60 months. Patients and Methods Between February 1996 and April 2000, 716 patients were entered onto this trial. Adjuvant treatment began within 6 weeks after surgery. Sequential treatment of CT administered first followed by RT was compared with concurrent treatment of CT administered with RT. The CT regimen consisted of mitoxantrone (12 mg/m2), fluorouracil (500 mg/m2), and cyclophosphamide (500 mg/m2) on day 1, and it was repeated every 21 days for six courses. RT was delivered to the breast and, when indicated, to the regional lymphatics. Results There was no statistically significant difference in treatment in the 5-year DFS (80% in both groups; P = .83), locoregional recurrence-free survival (LRFS; 92% in sequential v 95% in concurrent; P = .76), metastasis-free survival (87% in sequential v 84% in concurrent; P = .55), or overall survival (90% in sequential v 91% in concurrent; P = .76). Nevertheless, in the node-positive subgroup, the 5-year LRFS was statistically better in the concurrent arm (97% in concurrent v 91% in sequential; P = .02), corresponding to a risk of locoregional recurrence decreased by 39% (hazard ratio, 0.61; 95% CI, 0.38 to 0.93). Conclusion This treatment protocol remains an appealing clinical option for many women with operable breast cancer at a high risk of recurrence. Combination treatments with new drugs for breast cancer are warranted.
Several randomized trials with very long follow-ups have established that breast-conserving therapy and mastectomy share equivalent outcomes in terms of overall survival (OS).1-3 Breast-conserving therapy (ie, breast-conserving surgery [BCS] followed by a course of postoperative radiotherapy [RT]) is now considered to be the current standard of care for patients with early operable breast cancer.4 In addition, the impact of adjuvant chemotherapy (CT) has been convincingly demonstrated in high-risk breast cancer patients, namely with involved axillary nodes, in terms of disease-free survival (DFS) and OS rates.5 Even if the administration of adjuvant CT before RT has become common practice in women with early-stage breast cancer who undergo conservative surgery, the optimal integration of CT and RT is still controversial. In this setting, a prospective randomized trial was designed to determine the influence of sequencing RT and CT on doses of CT delivered, cosmetic outcome, and DFS. With a median follow-up of 58 months, the initial results suggested that for patients with a substantial risk of systemic metastases, it was preferable to give a 12-week course of CT followed by RT, rather than RT followed by CT.6 In contrast, an updated analysis of this trial with a median follow-up of 135 months in surviving patients recently showed no statistically significant difference in the rates of freedom from any event or OS between the CT-first and RT-first arms.7 In high-risk breast cancer, concurrent administration of both treatments is feasible using selected drugs that should not have cumulative toxic effects with RT. Such a scheme may have the advantage of providing a synergistic effect on tumor response8,9 and shortening the delay in starting RT with survival benefits.10,11 In 1996, a French multicenter phase III randomized trial was initiated to compare the effect on DFS of concurrent versus sequential fluorouracil, novantrone, and cyclophosphamide (FNC) CT and RT after BCS for stages I and II breast cancer. This report presents the clinical results with a median follow-up of 60 months (range, 3 to 105 months).
The protocol was approved by each local institutional review board, and written informed consent was obtained from all patients.
Patient Selection and Treatment Plan Patients were required to have undergone complete gross excision of the primary tumor. Surgical margins had to be negative before randomization. Patients with prior ipsilateral breast/axillary radiation, ipsilateral breast reconstruction, augmentation/reduction mammoplasty, or synchronous bilateral breast tumors were excluded. All patients had staging investigations, including chest x-ray, bone scan, and a test of liver enzymes to rule out metastatic disease at diagnosis. BCS with axillary dissection was performed in all patients. According to the protocol, adjuvant treatment began within 6 weeks after surgery and compared sequential treatment with CT administered first followed by RT versus CT administered concurrently with RT. RT was delivered to the breast and, when indicated, to the regional lymphatics. Treatment portals consisted of opposing tangential fields using cobalt or 6- to 10-MV photons. Both tangential fields were treated daily. The breast dose, routinely prescribed to the midline, was 50 Gy in 2-Gy fractions, with a varying percentage of compensating filters and/or bolus. A 10- to 20-Gy RT boost to the primary tumor bed using electrons, photons, or brachytherapy was delivered at the discretion of each participating center. The lateral decubitus treatment position was used in patients with voluminous or pendulous breasts in some institutions.13 Nodal irradiation (mostly to supraclavicular nodes and internal mammary chains [IMCs]) was given at a total dose of 50 Gy in 25-Gy fractions in node-positive patients and in the case of central or medial tumor locations. IMC RT was left at the discretion of local RT guidelines, as its use was commonly approved in France, even in the absence of a randomized trial. The CT regimen consisted of mitoxantrone (12 mg/m2), fluorouracil (500 mg/m2), and cyclophosphamide (500 mg/m2) on day 1, and it was repeated every 21 days for six courses. In the sequential arm, RT started 3 to 5 weeks after the sixth cycle of CT. In the concurrent arm, RT started the day of the first CT cycle. An absolute granulocyte count of less than 1,500/mm3 or a platelet count of less than 100,000/mm3 on day 21 resulted in a treatment delay of at least 1 week. Treatment was stopped if hematologic recovery took more than 5 weeks. No dose reductions were planned. RT was interrupted if grade 3 cutaneous toxicity occurred. Post- or perimenopausal women who were shown to have estrogen receptor–positive and/or progesterone receptor-positive tumors were prescribed 20 mg daily of tamoxifen, which was started during or after RT at the discretion of the treating physician.
Follow-Up and End Points
Statistical Analysis At a 1:1 ratio, women were randomly assigned to receive concurrent or sequential CT and RT. The participating center and axillary node status were the two initially planned stratification criteria. Random assignment was performed at the Biostatistics Unit at Centre Hospitalier Universitaire (Tours, France).
Qualitative differences between the two groups of patients were tested by the The Kaplan-Meier method was used to estimate the rates of DFS, locoregional recurrence-free survival (LRFS), metastasis-free survival (MFS), and OS. The log-rank test was used to evaluate the differences between the groups. All randomly assigned patients were included in the assessment of the primary end point (an intention-to-treat analysis).
Patient Characteristics Between February 1996 and April 2000, 716 eligible women were enrolled onto the trial (Fig 1). Three hundred fifty-eight were randomly assigned to receive sequential CT and RT, and 358 were assigned to receive concurrent CT and RT. Twenty-one patients were ineligible and excluded from the current analysis. The clinical and pathologic features of the two groups of patients are presented in Tables 1 and 2. The main baseline characteristics of the two groups were similar. Involved tumor margins were found more in the sequential arm (36 v 20; P = .03), whereas margin invasion with ductal carcinoma in situ was seen more in the concurrent arm (28 v 44; P = .08). Estrogen or progesterone receptors were positive in the tumors of 462 women (69%), and both types of receptors were negative in 205 women (31%). Of the whole group, 287 women (41%) were menopausal, 401 (58%) were premenopausal, and seven (1%) had an unknown menopausal status.
Treatment Compliance There was no difference observed between the two arms in terms of type of surgery, mainly tumorectomy and quadrantectomy (P = .40; Table 3).
As previously reported, the median CT dose was similar in the two arms.11 Median time to complete CT was not significantly longer in the concurrent arm (16.3 weeks) than in the sequential arm (16 weeks; P = .09; Table 3). Ninety-three percent of patients in the sequential arm and 88% of patients in the concurrent arm received the six planned CT courses (P = .36). The relative dose-intensity of each drug component was significantly lower in the concurrent arm compared with the sequential arm.15 Details of RT are presented in Table 3. For patients who received a boost, the total dose did not differ from the two treatment arms (61.4 Gy in the sequential arm v 62.2 Gy in the concurrent arm; P = .11). Twelve patients in the sequential arm and another two in the concurrent arm (P = .002) never received RT treatment. IMC irradiation was delivered in 72.6% and 71% of the patients in the sequential and concurrent arms, respectively (P = .26). RT treatment had to be interrupted in 123 patients overall, for varying reasons, without a difference between the two arms. Acute locoregional toxicities were moderate in both arms. Esophagitis was more frequent in the concurrent arm (115 v 89; P = .04). Acute systemic symptoms also were mild in both arms. Nausea/vomiting was significantly higher in the sequential treatment arm (248 v 235; P = .008), whereas anemia was significantly more frequent in the concurrent arm (111 v 81; P = .02). The assessment of late toxicities was published recently for 214 assessable patients.14 Subcutaneous fibrosis, telangectasia, skin pigmentation, and breast atrophy were significantly increased in the concurrent arm. No statistical difference was observed between the two arms concerning grade 2 or greater pain, breast edema, and lymphedema. One patient in each arm developed acute myelogenous leukemia in the first 18 months after treatment.
Outcomes
During the entire follow-up period, 25 (7.3%) of 343 patients in the sequential arm experienced local recurrence as the first site of recurrence compared with 16 (4.5%) of 352 patients in the concurrent arm. LRFS was not statistically different between the arms in the node-negative subgroup (93% in both groups; P = .81; Fig 3A). Nevertheless, in the node-positive subgroup (n = 389), concurrent RT and CT significantly decreased the risk of locoregional recurrence by 39% (hazard ratio, 0.61; 95% CI, 0.38 to 0.93; Fig 3B). The 5-year LRFS was statistically better in the concurrent arm (97%) compared with the sequential one (91%; P = .02).
In the node-negative subgroup, the crude number of patients who recurred were similar—eight of 152 in the sequential arm and nine of 154 in the concurrent arm. In contrast, locoregional recurrences were observed in the node-positive subgroup at the last follow-up in 17 of 191 patients in the sequential arm and seven of 154 patients in the concurrent arm. Among the patients, nine of 17 in the sequential arm and three of seven in the concurrent arm died from their breast cancer. Forty-six (13.4%) of 343 patients in the sequential arm experienced a distant or regional metastasis at their first site of recurrence compared with 59 (16.8%) of the 352 patients in the concurrent arm (P = .26). Thirteen (3.8%) of the 343 patients in the sequential arm and 11 (3.1%) of the 352 patients in the concurrent arm experienced a contralateral breast cancer as their first experience of treatment failure. In the sequential and concurrent arms, 271 (79%) and 278 (79%) patients, respectively, remained alive without evidence of disease.
RT and CT have established roles in the multidisciplinary management of early-stage breast cancer.4,5 Several retrospective reports have suggested that delaying the initiation of RT for more than six months after surgery might increase the risk of locoregional recurrence.16 The initial results of the Joint Center for Radiation Therapy Trial (JCRT)6 confirmed these findings and published with a median follow-up time of 58 months a borderline statistical significance (P = .07) in the 5-year crude rates of first recurrence according to the site. The regional recurrence was 5% and 14% in the RT-first and the CT-first arms, respectively. At that time, we decided to introduce RT earlier in the adjuvant treatment program to shorten duration of therapy and, thus, to improve efficacy.
We opened the ARCOSEIN trial and enrolled 716 patients in 4 years. To our knowledge, this is the largest phase III randomized trial evaluating the impact of concurrent RT and CT in early-stage breast cancer after BCS. Recently, two other European randomized studies17,18 compared concurrent and sequential RT and CT after surgery with a smaller number of patients. In the Italian trial,17 a total of 206 patients were randomly assigned to concurrent or sequential RT. The protocol treatment after quadrantectomy and positive/negative axillary dissection for breast cancer was adjuvant CT (cyclophosphamide, methotrexate, and fluorouracil [CMF]). The sample size was calculated to show a difference of 7% in the 5-year freedom from breast cancer recurrences. In the other trial,18 638 patients with prior breast surgery (416 BCS) and positive axillary dissection were randomly assigned to receive concomitant RT and CT (FNC regimen) or CT (fluorouracil, epirubicin, and cyclophosphamide) followed by RT. In this trial, 650 patients were estimated necessary to show a 10% improvement in 5-year DFS. Our randomized study presents 716 patients, all treated with BCS. The sample size was calculated to show a difference in DFS at 5 years that was We did not show any difference in DFS (P = .6) between the two arms for the population as a whole. The two other randomized trials17,18 also failed to show a statistical difference in their respective primary end points. Despite these results, we are still convinced that concurrent RT and CT may be beneficial to a subgroup of patients. With a short median follow-up of 60 months, we identified a significant decrease in the risk of locoregional recurrence by 39% (hazard ratio, 0.61; 95% CI, 0.38 to 0.93) with concurrent RT and CT for node-positive patients (who completed both CT and RT; n = 389). Rouëssé et al18 showed a 2.8-fold increased risk of locoregional recurrence in the subgroup of patients treated with BCS and randomly assigned to the sequential arm. In contrast, Arcangeli et al17 showed no difference in local recurrence rates according to sequence, but this trial is certainly underpowered to answer these questions. In our trial, there was no statistically significant treatment difference in MFS (P = .29) or OS (P = .54). The 5-year rates of death were acceptable and, in both arms, 9.6%. The impact of the exact surgery-to-CT interval on distant outcome is still under debate. Rouëssé et al18 did not detect any statistical differences at 5 years in metastatic relapses or in breast cancer deaths.18 In the update of the JCRT randomized trial,7 the average ratio of distant failure hazards (the CT-first arm divided by the RT-first arm) was 2.27 after 5 years, whereas it was 0.71 in the preliminary results with a median follow-up time of 58 months.6 Nodal status may modulate the impact of the surgery-to-CT interval on the risk of distant failure.16 With positive nodes, margin status is the second factor that may benefit from concurrent RT and CT. In daily practice, even if patients with positive surgical margins are no longer accepted for breast conservation, some patients refused a second surgery anxious of the risk of mastectomy. In our trial, margin invasion with infiltrative and ductal carcinoma in situ cells were more often found in the sequential and concurrent arms, respectively, which may reduce the impact of the results. In the JCRT trial,16 there was a substantial increase in the risk of local failure for patients with close or unknown resection margins assigned to the CT-first arm. The margin status may thus reflect the residual tumor burden after surgery and may explain the positive impact of starting RT earlier in the adjuvant treatment program. The main limitation of the ARCOSEIN trial is the use of mitoxantrone, a CT regimen not used in 2006. When patient entry onto this study began, mitoxantrone was used for treatment of metastatic breast cancer.19 An FNC regimen was prospectively compared with CMF in node-positive breast cancer patients in the adjuvant setting and showed a 5-year survival of 66% similar to those obtained (60%; P = .31) in the CMF arm.20 In addition, anthracycline administered concurrently with RT showed a high incidence of severe skin dermatitis and esophagitis, as reviewed in Recht et al16. Contrary to mitoxantrone, anthracycline regimens provoke free-radical production that may potentiate normal tissue reactions through a synergistic effect with free radicals induced by ionizing radiation. In our trial, acute locoregional toxicities were moderate in the two arms. Rouëssé et al18 presented more frequent grade 2 cutaneous toxicities in the concomitant arm, but this affected neither the RT schedule nor the 3-year cosmetic results. Very long-term toxicities (mainly esophageal, cardiac, and cutaneous) will be evaluated in a few years' time, with particular mention of the frequent use of IMC RT in this trial. The occurrence of secondary leukemia after administration of anthracenediones is now a well-recognized adverse effect.21 In our study, two cases of acute myeloblastic leukemia, one in each arm, were reported. This was much less than the 3.9% previously published21 for a cumulative dose of 56 mg/m2 or more, and it was similar to data published by Rouëssé et al.18 Taxanes are now increasingly used as adjuvant therapy for early-stage breast cancer,22-24 with a potent radiosensitizing effect through cell cycle arrest at the G2-M junction.25,26 Preliminary results are promising without unacceptable acute toxicities when taxanes are delivered concurrently with RT.27,28 More trials are needed to draw a definitive conclusion on safety using this RT and CT regimen, particularly with regard to pneumonitis.29 In conclusion, we identified a significant decrease in the risk of locoregional recurrence by 39% in concurrent RT and CT for node-positive patients. The finding that this subset of patients is already showing a significant difference could just be a sign in the direction of OS improvement, as patients with a faster natural history of the disease have already had the opportunity "to play out" their outcome (ie, a difference) at the current follow-up. It is perhaps much too early to draw conclusions about the others.
The authors indicated no potential conflicts of interest.
Conception and design: Pascal Garaud, Alain Fourquet, Daniel Serin, Jean-François Bosset, Olivier Le Floch, Gilles Calais Financial support: Gilles Calais Administrative support: Gilles Calais Provision of study materials or patients: Alain Fourquet, Daniel Serin, Jean-François Bosset, Joelle Miny-Buffet, Anne Favre, Olivier Le Floch, Gilles Calais Collection and assembly of data: Alain Toledano, David Azria, Pascal Garaud, Gilles Calais Data analysis and interpretation: Alain Toledano, David Azria, Pascal Garaud, Alain Fourquet Manuscript writing: Alain Toledano, David Azria, Alain Fourquet, Gilles Calais Final approval of manuscript: Alain Toledano, David Azria, Pascal Garaud, Alain Fourquet, Daniel Serin, Jean-François Bosset, Gilles Calais
We thank Frances Godson for excellent editorial assistance, Marie-Hélène Calais for excellent technical assistance, and all the participating centers, particularly the different investigators, who enrolled patients onto this trial. The following institutions and investigators participated in the study: CHU Tours: Dr Reynaud-Bougnoux — CHU La Pitié-Salpetrière: Dr Simon — Polyclinique St Côme, Compiègne: Dr Pellae-Cosset; Dr Ciupa; Dr Gay — Clinique Hartmann, Neuilly/Seine: Dr Vannetzel — CHRU Marseille: Dr Lejeune — Hôpital Henri Mondor, Créteil: Dr Levy — Clinique St Catherine, Avignon: Dr Kisher; Dr Berger — Institut Curie, Paris: Pr Pouillard—Centre Léon Bérard, Lyon: Dr Helfre; Dr Sunyac'h — Hôpital Minjoz, Besançon: Pr Bosset; Dr Miny — Hôpital la Milleterie, Poitiers: Pr Daban; Dr Fruge — CHU St Etienne: Pr Schmitt; Dr Tabalard; Pr Perpoint — Clinique du Méridien, Cannes la Bocca: Dr Ramos — Centre Paul Papin, Angers: Dr Gamelin; Dr Minier; Dr Delva — Centre Eugène Marquis, Rennes: Dr Le Prisé; Dr Lesimple — Centre St Yves, Vanves: Dr Monpetit; Dr Vuillemin — CHU La Tronche, Grenoble: Pr Bolla; Pr Mousseau — Clinique du Tonkin, Villeurbanne: Dr Guyon; Dr Chabert; Dr Hallonet; Dr Servajean; Dr Buatois; Dr Jaussaud; Dr Mere — Hôpital de Chambéry: Dr Cretinon; Dr Froger — Clinique de radiothérapie du Parc, Dijon: Dr Janoray- Clinique Guillaume le Conquérant, Le Havre: Dr Oudinot — Centre d'Oncologie de Ris Orangis: Dr Maltere; Dr Gautier; Dr Malamud — CHU Caremeau, Nîmes: Dr Bons Rosset — Centre Antoine Lacassagne, Nice: Dr Tessier; Pr Namer; Dr Ferrero — Centre Hospitalier La Source, Orléans: Dr Breteau; Dr Avogor; Dr Lucas; Dr Renaud — Centre Jean Perrin, Clermont Ferrand: Dr Achard — Centre hospitalier résidence du Parc, Marseille: Dr Dalivoust; Dr Aimard — Clinique St Pierre, Perpignan: Dr Castéra — Polyclinique Fleming, Tours: Dr Cailleux; Dr Maillet.
Presented in part at the Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 16-20, 2005, Denver, CO. Both A.T. and D.A. contributed equally to this work. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Veronesi U, Cascinelli N, Mariani L, et al: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347:1227-1232, 2002 2. Fisher B, Anderson S, Bryant J, et al: Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 347:1233-1241, 2002 3. van Dongen JA, Voogd AC, Fentiman IS, et al: Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organisation for Research and Treatment of Cancer 10801 trial. J Natl Cancer Inst 92:1143-1150, 2000 4. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005[Medline] 5. Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 6. Recht A, Come SE, Henderson IC, et al: The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334:1356-1361, 1996 7. Bellon JR, Come SE, Gelman RS, et al: Sequencing of chemotherapy and radiation therapy in early-stage breast cancer: Updated results of a prospective randomized trial. J Clin Oncol 23:1934-1940, 2005 8. Steel GG, Peckham MJ: Exploitable mechanisms in combined radiotherapy-chemotherapy: The concept of additivity. Int J Radiat Oncol Biol Phys 5:85-91, 1979[Medline] 9. Steel GG: Terminology in the description of drug-radiation interactions. Int J Radiat Oncol Biol Phys 5:1145-1150, 1979[Medline] 10. Mikeljevic JS, Haward R, Johnston C, et al: Trends in postoperative radiotherapy delay and the effect on survival in breast cancer patients treated with conservation surgery. Br J Cancer 90:1343-1348, 2004[CrossRef][Medline] 11. Calais G: Radiation and concomitant chemotherapy after surgery for breast cancer. Cancer Radiother 8:39-47, 2004[Medline] 12. Singletary SE, Allred C, Ashley P, et al: Revision of the American Joint Committee on Cancer staging system for breast cancer. J Clin Oncol 20:3628-3636, 2002 13. Campana F, Kirova YM, Rosenwald JC, et al: Breast radiotherapy in the lateral decubitus position: A technique to prevent lung and heart irradiation. Int J Radiat Oncol Biol Phys 61:1348-1354, 2005[CrossRef][Medline] 14. Toledano A, Garaud P, Serin D, et al: Concurrent administration of adjuvant chemotherapy and radiotherapy after breast-conservative surgery enhances late toxicities: Long-term results of the Arcosein multicenter randomized study. Int J Radiat Oncol Biol Phys 65:324-332, 2006[CrossRef][Medline] 15. Calais G: Radiation and concomitant chemotherapy after surgery for breast cancer: Arcosein study. Cancer Radiother 2:469-474, 1998[Medline] 16. Recht A: Integration of systemic therapy and radiation therapy for patients with early-stage breast cancer treated with conservative surgery. Clin Breast Cancer 4:104-113, 2003[Medline] 17. Arcangeli G, Pinnaro P, Rambone R, et al: A phase III randomized study on the sequence of radiotherapy and chemotherapy in the conservative management of early-stage breast cancer. Int J Radiat Oncol Biol Phys 64:161-167, 2006[CrossRef][Medline] 18. Rouëssé J, De la Lande B, Bertheault-Cvitkovic F, et al: A phase III randomized trial comparing adjuvant concomitant chemoradiotherapy versus standard adjuvant chemotherapy followed by radiotherapy in operable node-positive breast cancer: Final results. Int J Radiat Oncol Biol Phys 64:1072-1080, 2006[CrossRef][Medline] 19. Cowan JD, Neidhart J, McClure S, et al: Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: A Southwest Oncology Group study. J Natl Cancer Inst 83:1077-1084, 1991 20. Isacson R, Safra T, Ben-Dor G, et al: A preliminary report of a pilot randomised trial comparing cyclophosphamide, methotrexate and 5-fluorouracil with cyclophosphamide, mitoxantrone and 5-fluorouracil in the adjuvant therapy of stage II breast cancer with four or more positive axillary nodes. Anticancer Drugs 4:189-192, 1993[Medline] 21. Chaplain G, Milan C, Sgro C, et al: Increased risk of acute leukemia after adjuvant chemotherapy for breast cancer: A population-based study. J Clin Oncol 18:2836-2842, 2000 22. Martin M, Pienkowski T, Mackey J, et al: Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352:2302-2313, 2005 23. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, et al: Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354:809-820, 2006 24. Mamounas EP, Bryant J, Lembersky B, et al: Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: Results from NSABP B-28. J Clin Oncol 23:3686-3696, 2005 25. Hennequin C, Giocanti N, Favaudon V: Interaction of ionizing radiation with paclitaxel (Taxol) and docetaxel (Taxotere) in HeLa and SQ20B cells. Cancer Res 56:1842-1850, 1996 26. Milas L, Milas MM, Mason KA: Combination of taxanes with radiation: Preclinical studies. Semin Radiat Oncol 9:12-26, 1999[Medline] 27. Formenti SC, Volm M, Skinner KA, et al: Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin-based chemotherapy in locally advanced breast cancer: A phase I/II trial. J Clin Oncol 21:864-870, 2003 28. Ellerbroek N, Martino S, Mautner B, et al: Breast-conserving therapy with adjuvant paclitaxel and radiation therapy: Feasability of concurrent treatment. Breast J 9:74-78, 2003[CrossRef][Medline] 29. Burstein HJ, Bellon JR, Galper S, et al: Prospective evaluation of concurrent paclitaxel and radiation therapy after adjuvant doxorubicin and cyclophosphamide chemotherapy for stage II or III breast cancer. Int J Radiat Oncol Biol Phys 64:496-504, 2006[CrossRef][Medline] Submitted June 13, 2006; accepted November 3, 2006.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
of .05 and a statistical power of 80% or greater). 
2 test (with a possible Monte-Carlo correction for rare events) or the log-likelihood ratio significance test (G test), though differences in quantitative measurements were tested by either the t test or Mann-Whitney test (depending on the distribution characteristics). 
10% between the two arms. 
