Japanese Journal of Clinical Oncology 33:563-569 (2003)
© 2003 Foundation for Promotion of Cancer Research
The Sequencing of Radiation Therapy and Chemotherapy after Mastectomy in Premenopausal Women with Breast Cancer
1 Department of Radiation Oncology and 2 Department of Pathology, Ondokuz Mayis University, Medical School, Samsun, Turkey
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Objective: The purpose of this study was to evaluate the prognostic importance of the sequencing of radiation therapy and chemotherapy after mastectomy in high-risk premenopausal women with breast cancer in addition to other known prognostic factors in the literature.
Methods: In this retrospective study, 176 premenopausal women with breast cancer were evaluated. The median age at referral was 39 years (range, 28–59 years); 106 patients had stage II and 70 had stage III disease. All were subjected to mastectomy. The median number of lymph nodes removed was 19. The influence of age, histological grade, number of nodes removed, number of positive nodes, tumor size, estrogen receptor status, lymphovascular invasion and sequencing of radiotherapy and chemotherapy on 5-year locoregional disease-free survival, 5-year systemic disease-free survival, 5-year disease-free survival and 5-year cancer-specific survival were studied.
Results: The 5-year locoregional disease-free survival was 94% for the entire patient population. Because of the small number of locoregional recurrences, none of the evaluated factors was prognostically significant for locoregional recurrence. The 5-year systemic disease-free, disease-free and cancer-specific survival rates were 72, 70 and 77%, respectively. On multivariate analysis of host, tumor and treatment-related factors, the number of positive nodes [RR 1.9 (95% CI: 1.36–2.63), RR 2 (1.46–2.84 ) and RR 1.8 (1.3–2.71), respectively], histopathological grade [RR 1.8 (95% CI: 1.24–2.65), RR 1.9 (1.34–2.88), RR 2.5 (1.65–4.07), respectively], estrogen receptor status [RR 3.5 (95% CI: 1.5–8.6), RR 3.9 (1.64–9.41), RR 2.5 (1.05–6.24), respectively] and the sequencing of radiotherapy and chemotherapy [RR 1.6 (95% CI: 1.17–2.39), RR 1.7 (1.25–2.54), RR 1.6 (1.14–2.43), respectively] were all significant independent predictors of outcome.
Conclusions: Our results show that in addition to traditional prognostic factors, the sequencing of radiation therapy and chemotherapy also predict for increased risk of any type of recurrence or further tumor death.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The determination of the optimal sequencing of radiotherapy (RT) and chemotherapy (CT) after mastectomy or breast-conserving surgery is an extremely timely topic in patients with breast cancer. Randomized trials evaluating the value of optimal sequencing of RT and CT have shown that delaying RT for several months after breast-conserving surgery until the completion of adjuvant systemic CT appears safe and may be preferable for patients at high risk of distant dissemination (1–3).
Historically, most institutions have delivered CT followed by RT in post-mastectomy patients. This conventional sequencing is based on the ability of CT to reduce metastatic spread in women with positive and negative nodes and the lack of a survival benefit from the use of post-mastectomy radiotherapy (PMRT). However, this argument may not hold, given the recent findings of PMRT trials. A meta-analysis of 18 randomized trials, which included results from Danish trials, revealed a decrease in overall mortality in premenopausal women who received PMRT (4–7). The question of whether conventional sequencing is optimal is intriguing, especially given that Danish and British Columbian trials yielded significant survival benefit in favor of RT in which RT was delivered between successive cycles of drugs rather than at the completion of CT (8).
The purpose of this study was to evaluate the prognostic importance of the sequencing of RT and CT after mastectomy in high-risk premenopausal women with breast cancer in addition to other known prognostic factors in the literature.
|
PATIENTS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Patients’ Characteristics
Between 1993 and 1997, 197 premenopausal women with breast cancer were treated by PMRT and CT in our institution. The median age at referral was 39 years (range, 28–59 years). Twenty-one patients were censored from this analysis for the following reasons: death from congestive heart failure at <3 months following therapy (n = 1) and patient records which lacked pertinent information (n = 20). For the remaining 176 patients, the minimum follow-up was 9 months, the median was 63 months and the maximum was 101 months.
The primary surgical treatment, performed by specialists, was mastectomy and axillary dissection. Six patients had radical mastectomy (RM), 136 had modified radical mastectomy (MRM) and 34 had total mastectomy (TM).
Overall, a median of 19 lymph nodes were removed. The specimens and histopathological slides of all the tumors were reviewed by the same pathologist. All of the 176 patients had infiltrating ductal carcinomas according to the WHO histological typing system (9). Tumor histopathological grade was scored as grade I (n = 44), grade II (n = 62) or grade III (n = 70) according to the system of Bloom and Richardson (10). Six patients had T1 tumors, 106 had T2, 56 had T3 and eight had T4 disease according to the UICC staging system (11). The median tumor size as measured pathologically was 4 cm, range 1.5–6 cm. Thirty-eight patients had estrogen receptor (ER)-positive disease and 138 patients had ER-negative disease. Of the 176 patients, 52 had peritumoral lymphatic and/or vascular invasion.
Post-mastectomy Radiotherapy
PMRT was used for patients who had one or more of the following: positive axillary lymph nodes or gross extracapsular tumor extension, a tumor size of >4 cm, invasion of the cancer to skin, pectoral fascia or skeletal muscle, positive or very close surgical margins, undifferentiation of tumor, peritumoral lymphatic and/or vascular invasion (LVI).
Radiotherapy first, followed by four or six cycles of CT, was given to 40 patients; and CT first was given 136 patients. Of the 136 patients who were given CT first, 82 received three cycles of CT first, followed by RT and three additional cycles of CT (sandwich therapy); and 54 received six cycles of CT first, followed by RT. For patients who were treated with CT first, RT started within 2 weeks after the third or sixth cycle of CT. They completed the RT within 5 weeks and, after a rest of 2 weeks, continued with the CT regimen. The median interval between the breast surgery and the start of radiotherapy was 12 weeks, range 3–20 weeks (4 weeks for the RT-first group and 20 weeks for the CT-first group).
In all patients, megavoltage equipment was used, with a cobalt-60 unit. Radiotherapy was delivered to the chest wall, including the surgical scar and regional lymph nodes (i.e. supraclavicular, infraclavicular and axillary nodes as well as internal mammary nodes). The chest wall was irradiated through two tangential fields and received a median absorbed dose in the target volume of 50 Gy, given in 25 fractions over a period of ~5 weeks. The regional lymph nodes were irradiated through an anterior axillary–internal mammary–supraclavicular field and received a dose of 50 Gy at a depth of 3 cm. The mid-axilla received a dose of 50 Gy through direct anterior field with a posterior axillary boost. All the fields were treated daily and immobilization techniques were used as required. Treatment duration ranged from 33 to 40 days. The majority of the 176 patients completed their treatment without interruption.
Chemotherapy
Patients who had 
3 positive nodes and cardiac disease were treated with a combination of cyclophosphamide (600 mg/m2 body surface area, day 1), methotrexate (40 mg/m2, day 1) and fluorouracil (600 mg/m2, day 1), intravenously (i.v.) every 4 weeks. The remaining patients were treated with a combination of cyclophosphamide (500 mg/m2 i.v., day 1), adriamycine (50 mg/m2 i.v., day 1) and fluorouracil (500 mg/m2 i.v., days 1 and 8), every 4 weeks. Thirty-eight patients who had ER-positive disease also received tamoxifen (20 mg per day) in addition to CT.
Follow-up
Patients were followed up with clinical examination 1 month after completing RT and CT, every 3 months during the first 3 years and every 6 months thereafter. Follow-up chest radiography, blood studies and imaging studies were performed as required.
End Points
We studied the following end points: Any locoregional recurrence (LRR) (chest wall or regional lymphatics) for the analysis of locoregional disease-free survival; any systemic relapse for systemic disease-free survival; any relapse of breast cancer (locoregional or systemic relapse) for the analysis of disease-free survival; death from breast cancer for the analysis of breast cancer-specific survival.
Complications
Chemotherapy complications were evaluated according to the Common Toxicity Criteria (CTC) (12).
Statistical Analysis
Survival curves were constructed using the Kaplan–Meier method with statistical significance assessed by the log-rank test. Univariate and multivariate analysis were performed using the Cox logistic regression method (13). All P values were two-tailed; a value of 0.05 was considered significant. The date for the evaluation of recurrence and survival was February 1, 2003, so that the median potential follow-up was 63 months. The patient, tumor and treatment-related variables studied are detailed in Table 1.
|
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Locoregional Disease-free Survival
Twelve patients experienced LRR during the time period studied. The median time to LRR was 25 months from the first treatment date (range, 17–62 months). Only three recurrences occurred in the regional lymphatics; the remainder lay within the chest wall. Regional involvement included lymph nodes in the supraclavicular (n = 2) and axillar regions (n = 1).
The 5-year locoregional disease-free survival was 94%. On univariate analysis, histological grade, number of nodes removed and patient age were significant independent predictors of outcome (Table 1). On multivariate analysis, none of the evaluated factors was prognostically significant for locoregional recurrence (Table 2). Only a non-significant trend towards increased risk of locoregional recurrence in patients 10 nodes removed when compared with those 
11 (P = 0.0558) was found.
|
Systemic Disease-free Survival
Fifty-four patients experienced disease recurrence at distant sites. Among patients experiencing distant recurrence, the median time to metastasis was 27 months (range, 7–83 months). Sites of involvement with metastatic breast cancer included the lung only (n = 22), bone only (n = 19), liver only (n = 3), brain only (n = 1), adrenal gland only (n = 1), lung with bone (n = 3), brain (n = 2) and liver (n = 2) and liver with bone (n = 1).
The 5-year systemic disease-free survival was 72% for the entire patient population. On both univariate and multivariate analysis, the presence of 10 positive axillary nodes, grade III tumor, ER-negative disease and sandwich therapy, were independent poor risk factors for systemic recurrence (Tables 1 and 2).
Disease-free Survival
During the follow-up, breast cancer had recurred in 56 patients. The median time to recurrence was 27 months from the first treatment date (range 6–83 months). Of the 56 patients with recurrences, the disease returned locoregionally as a first event in 10 and systemically in 46 patients.
The 5-year disease-free survival was 70% for the entire patient group. On both univariate and multivariate analysis, the presence of 10 positive axillary nodes, grade III tumor, ER-negative disease and sandwich therapy were associated with increased risk of recurrence of any type (Tables 3 and 4). Patients delivered sandwich therapy had a higher risk of any type of recurrence than those delivered RT first followed by CT or CT first followed by RT (Fig. 1).
|
|
|
Cancer-specific Survival
Forty-eight patients with distant metastasis were dead of the disease at the time of this analysis. The median time to death was 39 months from the first treatment date (range 9–92 months).
The 5-year breast cancer-specific survival was 77%. On multivariate analysis, the presence of 10 positive axillary nodes, grade III tumor, ER-negative disease and sandwich therapy were independent poor risk factors for death from breast cancer (Table 4). Again, patients delivered sandwich therapy had a higher risk of dying of breast cancer compared with those delivered RT first followed by CT or CT first followed by RT (Fig. 2).
|
Complications
Radiotherapy
Twenty-eight patients developed transient complications. Seventeen of these patients had complications such as erythema and/or dry desquamation which did not require treatment. Eleven patients had early complications which required treatment. Four of these patients had moist desquamation and seven had symptomatic pneumonitis.
Nineteen patients developed late complications. There was arm edema in five patients, apical pulmoner fibrosis in 10 and telangiectasias in four.
Chemotherapy
No grade 3 or 4 toxicities were observed in any group. There is no statistically significant difference between the three groups for grade 1 and 2 toxicities. None of the evaluated factors was prognostically significant for complications.
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
The number of positive lymph nodes is the most important histological prognostic factor of both disease-free survival and overall survival in patients with breast cancer. The influence of positive axillary nodes on the outcome has been demonstrated in both patients treated with mastectomy and adjuvant systemic CT and patients treated with PMRT in addition to adjuvant systemic CT (5,6,10). This has also been documented in our study.
Despite being poorly reproducible in nature, it has been demonstrated that histological grade is an important prognostic factor (14,15). This was also documented in our study.
Another important histological prognostic factor in determining the outcome is tumor size (4,16). The findings of our study showed that tumor size was not a significant prognostic factor. This conclusion should be treated with caution because of the unequal sample size of groups of tumor size 2, 2–5 and 5 cm.
Although estrogen receptor status correlates with prognosis, it does so only weakly. Furthermore, several studies have reported that estrogen receptor is a prognostic factor for 5-year disease-free survival, although the curves tend to merge with longer follow-up (17,18). In our study, ER-negative disease, in agreement with other studies, was a poor risk factor for any type of recurrence.
Locoregional control of breast cancer following RT and CT may be a function of interrelated patient, tumor and treatment factors. However, the small number of locoregional recurrences made the identification of those which were most important by Cox regression modeling impossible in our study.
As is well known, axillary dissection is principally recognized as a prognostic, rather than therapeutic, procedure. It has been reported that at least 6–10 nodes need to be removed to avoid misclassification and to optimize local control. The number of axillary nodes removed in Danish trials was less (median, seven nodes) than that removed in US trials and the rates of locoregional recurrence, especially axillary recurrences, observed in these trials were greater than observed in the US series (4,5,19–22). In our study, patients with <10 nodes removed had a higher risk of locoregional recurrence than those with 11 nodes removed. However, the influence of number of nodes removed on locoregional control was not statistically significant (P = 0.0558).
Our results indicate that in addition to the traditional prognostic factors, the sequencing of RT and CT also predicts the risk of any type of recurrence or tumor death. Retrospective reviews of patients treated with either mastectomy or breast-conserving surgery examining the influence of the sequencing of RT and CT on outcome have shown conflicting results (23–26). Only one trial has been conducted specifically to evaluate the question of optimal sequencing after breast-conserving surgery (27). A multivariate analysis of factors affecting the results identified margin status and number of positive nodes as the only statistically significant factors predicting recurrence. To our knowledge, there has been no clinical trial specifically testing the effect of sequencing of RT and CT in post-mastectomy women.
A theoretical concern about the sandwich approach is that clones of tumor cells could grow during the period of RT, making the remaining cycles of CT ineffective. Although this is a valid concern, there are no clinical data to support it. In our study, a significant decrease was seen in disease-free survival in the arm using sandwich therapy. The disease-free survival rates were 74% in the arm with RT first, 85% in the arm using CT first and 60% in the sandwich therapy arm (P = 0.001). Corresponding estimates for systemic disease-free survival were 75, 86 and 62%, respectively (P = 0.003). For cancer-specific survival, corresponding estimates were 84, 86 and 66%, respectively (P = 0.01).
However, our study is not a randomized trial. The poor results in the sandwich arm may be related to the patient selection; patients with 10 positive axillary nodes, grade III tumor and ER-negative disease. It may also be due to the chemotherapy regimens used. Hence we detected the patient characteristics and chemotherapy regimens used in the sandwich arm taking these possibilities into account. The results are shown in Table 5. As can be seen, the distributions of the patients’ characteristics and the chemotherapy regimens used were grossly similar in all groups.
|
The patients group which constituted the basis of our analysis is relatively homogeneous. All 176 patients had stage II–III breast cancers and were treated by PMRT and adjuvant systemic CT. However, the number of patients is small and it was not a randomized study. Also, late recurrences, deaths and late complications such as cardiac toxicity will be missed because some of the patients had at least 5 years of follow-up. In addition to the presence of
10 positive axillary nodes, high tumor grade, ER-negative disease and the sequencing of RT and CT significantly affected any type of recurrence or tumor death in this group of patients. In conclusion, our results indicate that in addition to traditional prognostic factors, the sequencing of RT and CT also predicts for outcome and that sequential therapy using CT followed by RT or RT followed by CT may result in improved overall survival, compared with sandwich therapy.
|
FOOTNOTES |
|---|
+ For reprints and all correspondence: Bilge Gursel, Department of Radiation Oncology, Ondokuz Mayis University, Medical School, 55139 Kurupelit, Samsun, Turkey. E-mail: bgursel{at}omu.edu.tr
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
1 Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, et al. Two months of doxorubicin–cyclophosphamide, methotrexate and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the national surgical adjuvant breast and bowel project B-15. J Clin Oncol 1990;8:1483–96.[Abstract]
2 International Breast Cancer Study Group. Duration and reintroduction of adjuvant chemotherapy for node-positive premenopausal breast cancer patients. J Clin Oncol 1996;14:1885–94.
3 Wallgren A, Bernier J, Gelber RD, Goldhirsch A, Roncadin M, Joseph D, et al. Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer. Int J Radiat Oncol Biol Phys 1996;35:649–59.[CrossRef][Web of Science][Medline]
4 Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, et al. Postoperative radiotherapy in high risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949–55.
5 Overgaard M, Jensen M-B, Overgaard J, Hansen PS, Rose C, Andersson M, et al. Postoperative radiotherapy in high risk postmenopausal breast cancer patients given adjuvant tamoxifen. Lancet 1999;353:1641–8.[CrossRef][Web of Science][Medline]
6 Ragaz J, Jackson SM, Le N, Plenderleith IH, Spinelli JJ, Basco VE, et al. Adjuvant radiotherapy and chemotherapy in node positive premenopausal women with breast cancer. N Engl J Med 1997;337:956–62.
7 Whelan TJ, Julian J, Wright J, Jadad AR, Levine ML. Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis. J Clin Oncol 2000;18:1220–9.
8 Pierce LJ. Post-mastectomy radiotherapy: future directions. Semin Radiat Oncol 1999;9:300–4.[CrossRef][Web of Science][Medline]
9 Scarff RW, Torloni H. Histological Typing of Breast Tumours. Geneva: World Health Organization 1968.
10 Bloom HJG, Richardson WW. Histological grading and prognosis in breast cancer: a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer 1957;11:359–77.[Web of Science][Medline]
11 UICC (Union International Contre le Cancer). TNM Classification of Malignant Tumours. Heidelberg: Springer 1987;93–9.
12 Common Toxicity Criteria. NCIC Criteria Version December 1994 revised. http://www.eortc.be.
13 Dawson-Saunders B, Trapp RG. Basic and Clinical Biostatistics, Norwalk, CT: Appleton and Lange 1990;186–228.
14 Dalton LW, Page DL, Dupont WD. Histological grading of breast carcinoma. A reproducibility study. Cancer 1994;73:2765–71.[CrossRef][Web of Science][Medline]
15 Winer EP, Morrow M, Osborne CK, Harris JR. Malignant Tumors of the Breast. In: DeVita VT Jr, Hellman S, Rosenberg SA, editors. Cancer. Principles and Practice of Oncology, 6th ed. Philadelphia: Lippincott Williams and Wilkins 2001;1651–722.
16 Carter CL, Allen C, Henson DE. Relation of tumor size, lymph node status and survival in 24,740 breast cancer cases. Cancer 1989;63:181–7.[CrossRef][Web of Science][Medline]
17 Adami HO, Graffman S, Lindgren A, Sallstrom J. Prognostic implication of estrogen receptor content in breast cancer. Breast Cancer Res Treat 1985;5:293–7.[CrossRef][Web of Science][Medline]
18 Mason BH, Holdaway IM, Mullins PR, Yee LH, Kay RG. Progesterone and estrogen receptors as prognostic variables in breast cancer. Cancer Res 1983;43:2985–9.
19 Cuzick J, Stewart H, Rutqvist L, Houghton J, Edwards R, Redmond C, et al. Cause-specific mortality in long term survivors of breast cancer who participated in trials radiotherapy. J Clin Oncol 1994;12:447–53.[Abstract]
20 Early Breast Cancer Trialists’ Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000;355:1757–70.[CrossRef][Web of Science][Medline]
21 Recht A, Bartelink H, Fourquet A, Fowble B, Haffty BG, Harris JR, et al. Post-mastectomy radiotherapy: questions for the twenty-first century. J Clin Oncol 1998;16:2886–9.[Web of Science][Medline]
22 Fowble B. Post-mastectomy radiation: then and now. Oncology 1997;11:213–34.[Medline]
23 Hartsell WF, Recine DC, Griem KL, Murthy AK. Delaying the initiation of intact breast irradiation for patients with lymph node positive breast cancer increases the risk of local recurrence. Cancer 1995;76:2497–503.[CrossRef][Web of Science][Medline]
24 Leonard CE, Wood ME, Zhen B, Rankin J, Waitz DA, Norton L, et al. Does administration of chemotherapy before radiotherapy in breast cancer patients treated with conservative surgery negatively impact local control? J Clin Oncol 1995;13:2906–15.[Abstract]
25 McCormick B, Norton L, Yao TJ, Yahalom J, Petrek JA. The impact of the sequence of radiation and chemotherapy on local control after breast-conserving surgery. Cancer J Sci Am 1996;2:39–45.[Medline]
26 Buchholz TA, Austin-Seymour MM, Moe RE, Ellis GK, Livingston RB, Pelton JG, et al. Effect of delay in radiation in the combined modality treatment of breast cancer. Int J Radiat Oncol Biol Phys 1993;26:23–5.[Web of Science][Medline]
27 Recht A, Come SE, Henderson IC, Gelman RS, Silver B, Hayes DF, et al. The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 1996;334:1356–61.
Received June 23, 2003; accepted September 21, 2003
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||