- Email: [email protected]
The outcome of treatment of breast cancer in a developing country—Oman
ARTICLE IN PRESS The Breast (2004) 13, 139–145
THE
BREAST www.elsevier.com/locate/breast
ORIGINAL ARTICLE
The outcome of treatment of breast cancer in a developing countryFOman M. Al-Moundhri*, B. Al-Bahrani, I. Pervez, S.S. Ganguly, V. Nirmala, A. Al-Madhani, K. Al-Mawaly, C. Grant Medical Oncology Branch, Department of Medicine, College of Medicine, Sultan Qaboos University, P.O. Box 35, Al-Khod, PC 123, Sultanate of Oman
KEYWORDS Breast cancer; Oman; Developing country
Summary The aim of the present study was to evaluate the outcome of treatment of breast cancer in Oman with an analysis of clinico-pathological features, treatment modalities utilized, and prognostic factors. One hundred fifty-two breast cancer patients diagnosed between January 1996 and June 2002 were evaluated retrospectively. Their mean age was 48.5 (S.D.710.8) years, and 48% of the female patients were premenopausal. The mean tumor size according to pathology was 4.6 (S.D. 3.29) cm, and 34.9% and 15.8% of patients had stage III or IV disease, respectively. Only 26.3% of the patients had breast-conserving surgery, and neoadjuvant chemotherapy was underutilized. The overall 5-year relapse-free survival (RFS) and overall (OS) survival rates were 62% and 64%, respectively. On multivariate analysis, axillary lymph node involvement and tumor differentiation were predictive of RFS and OS, respectively. Thus, breast cancer patients in Oman present with advanced stages of the disease at younger ages than their counterparts in the West and have lower survival rates. Increasing awareness and the introduction of screening programs and of a multidisciplinary approach are essential in Oman and other developing countries to improve the outcome of treatment. & 2003 Elsevier Ltd. All rights reserved.
Introduction Breast cancer is the most common cancer in women throughout the world and remains a major health problem. The incidence and clinico-pathological features of breast cancer differ between the developing countries in Asia and Africa and Western industrialized countries. The incidence of breast *Corresponding author. Tel.: þ 968-9437301; fax: þ 968513419. E-mail address: [email protected] (M. Al-Moundhri).
cancer is relatively low in developing countries compared with Western nations; however, an increase in incidence has been observed.1–3 In Asia and Africa, breast cancer affects more younger women and girls than in the West and is often in advanced stages with aggressive behavior when the patients first present.4–9 Abundant data on the outcome of breast cancer treatment are available from industrialized countries, where the use of screening mammography and the refinement of treatment have resulted in a reduction in mortality.10,11 There are numerous study reports
0960-9776/$ - see front matter & 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2003.10.001
ARTICLE IN PRESS 140
describing the clinico-pathological features of breast cancer in developing countries; however, reports on outcome of treatment remain rare, especially from Arab countries.7–9,12 The Sultanate of Oman is a developing Asian Arabic country where breast cancer is the most common female cancer. It accounts for one of every five cancers detected in female subjects, with an age-standardized incidence rate of 15.6 per 100,000 of the Omani female population.13,14 As in many other developing countries, awareness is low, cultural barriers are strong, access to specialized units is late, and there are no early breast cancer detection programs in place, although upto-date treatment modalities are applied. The aim of this study was to report on the outcome of breast cancer treatment in Oman by analyzing the clinical and pathological features, the treatment modalities utilized, prognostic factors, and survival. These variables are compared and contrasted with those recorded in other developing and developed countries.
Patients and methods This retrospective study was based on retrieval of cases diagnosed with invasive breast cancer from the computerized hospital information system of the two main teaching hospitals in the Sultanate of Oman: Sultan Qaboos University Hospital and the Royal Hospital. The oncology units of the two hospitals are the only centers in the country to which patients with a suspected or confirmed diagnosis of cancer are referred for review and further management. The majority of the study cases were diagnosed and treated in the two hospitals, while a few were operated on elsewhere and subsequently referred. Thus, surgeons in the peripheral hospitals undertake the initial intervention independently. The histopathological data of all confirmed specimens were reviewed in the two teaching hospitals to ensure consistency of histopathological reporting. All staging investigations were also performed in the two hospitals, and in the majority of cases these included chest X-ray, CT scans of chest and abdomen, and bone scan because of the advanced stage at presentation. The medical and pathological records of all patients with confirmed diagnoses of invasive breast cancer in the period between January 1996 and June 2002 were reviewed, and a database was created. The variables included were: age, sex, date of diagnosis, menstrual status, right or left breast involvement, histopathological type, clinical
M. Al-Moundhri et al.
and pathological size of the tumor, clinical and pathological skin or nipple involvement, clinical axillary lymph nodes involvement, number of lymph node removed and pathologic involvement, tumor differentiation, estrogen and progesterone receptor expression, and clinical and pathological stage at presentation. The staging was carried out using the AJCC (TNM) Cancer Staging Manual.15 The surgical intervention (mastectomy vs. lumpectomy) and the use of chemotherapy (adjuvant or neoadjuvant) and of hormonal and radiotherapy treatments were determined, and noted. The length of follow-up, the date of any relapse, and the date of death, where applicable, were also obtained from the patients’ records. Overall survival (OS) time was measured from diagnosis to death, censored by the end of followup. Relapse-free survival (RFS) time was measured from diagnosis to relapse, censored by the end of follow-up. Deaths during follow-up from causes other than breast cancer were censored. Survival and relapse estimates were obtained and presented graphically using a Kaplan–Meier test, and comparisons were made using the log-rank test. The risk ratio was estimated with a univariate setup using Cox’s proportional hazard model for the following variables: age, menopausal status, primary tumor size, axillary lymph node status, tumor differentiation, and estrogen receptor status. The statistically significant factors in univariate analysis were tested with a multivariate setup using Cox’s model. All P-values reported are nominal two-sided values. The SigmaStat SigmaPlot-10 statistical analysis software was used for the data analysis.
Results Clinical and pathological features Table 1 summarizes the clinical variables and treatment modalities utilized in 152 patients diagnosed with invasive breast cancer and treated in the study period. The mean age of all patients was 48.5 (S.D.710.8) years; 48% of the female patients were premenopausal; 20.4% were 40 years of age or younger. The majority of patients (65.8%) underwent non-breast-conserving surgery with modified radical mastectomy. Neoadjuvant chemotherapy was administered to 20 patients (13.2%), who made up only 37.7% of the 53 patients with locally advanced disease. Adjuvant external-beam radiotherapy to the breast area was administered to 96 patients (63.1%). The radiotherapy was administered in
ARTICLE IN PRESS Treatment of breast cancer in a developing country
Table 1
141
Clinical variables and management of 152 patients with invasive breast cancer.
Clinical characteristics Gender Female Male Age r40 41–50 51–60 Z60 Menstrual status (Women) Premenopausal Postmenopausal Site of breast lesion Left Right Bilateral Surgery Modified radical mastectomy Lumpectomy and axillary lymph node dissection Lumpectomy or biopsy only Chemotherapyn Neoadjuvant (All received anthracycline (AC/FEC/FAC) regimens) Adjuvant Anthracycline (AC/FEC/FAC) regimens Anthracycline-like regimen (CNF) CMF AC-T T and H Radiotherapy Hormonal treatment Tamoxifen Goserelin
Number
Percentage
150 2
98.7 1.3
31 46 49 26
20.4 30.3 32.2 17.1
72 78
48 52
74 76 2
48.7 50 1.3
100 40 12
65.8 26.3 7.9
20 65 (17) 44 (13) 7 10 (3) 4 0 (1) 96 115 98 (14) 3
13.2 42.8 (11.2)
63.1 75.7 64.4 (9.3) 2
The numbers in brackets refer to patients with metastatic disease treated with chemotherapy and/or hormonal treatment. n A ¼ Adriamycin, C ¼ cyclophosphamide, E ¼ epirubicin, F ¼ 5-fluorouracil, H ¼ Herceptin, M ¼ mitoxantrone, M ¼ methotrexate, T ¼ taxol.
various other countries, as there are no radiotherapy facilities at all in Oman. The clinical and pathological staging is summarized in Table 2. The average clinical and pathological sizes of breast tumors were 5.4 cm (S.D. 3.86) and 4.6 cm (S.D. 3.29), respectively. Clinically, T3 and T4 lesions were found in 38 (25%) and 26 patients (17%), respectively, and only 22 (14.5%) patients had T1 lesions. Axillary lymph node dissection was performed in 120 patients (excluding neoadjuvant chemotherapy patients) and 33.3%, 24.2%, and 11.7% had 1–3, 4–9, and 10 or more positive nodes, respectively. Advanced breast cancer predominated with stages III and IV being present in 53 (34.9%) and 24 (15.8%) of the patients, respectively. Stage III was found to be still more frequent on pathological staging, being found in 41.7% of the patients who underwent
surgery. The histopathological sub-types of the tumors were as follows: ductal (134), lobular (10), medullary (5), mucinous (2), and tubular (1). The differentiation was scored as high, moderate, and poor in 54 (35.5%), 25 (16.4%), and 73 (48.1%) of the tumors, respectively. The receptor status was available for 107 patients (68%), and 62 (58%) and 57 (53.3%) of these expressed estrogen and progesterone receptors, respectively.
Analysis of survival and prognostic factors With a mean follow-up interval of 35.6 months, there were 37 deaths and six patients were lost to follow-up. There were 23 deaths in the nonmetastatic group and 14 in the metastatic group. Eighty-six of the 128 patients with non-metastatic
ARTICLE IN PRESS 142
Table 2
M. Al-Moundhri et al.
Clinical and pathological staging of patients with invasive breast cancer. Clinical stage (N ¼ 152)
Pathological stagen (N ¼ 120)
Number
Percentage
Number
Percentage
Primary tumor Tis T1 T2 T3 T4
2 22 64 38 26
1.3 14.5 42.1 25 17.1
2 12 66 32 8
1.7 10 55 26.7 6.6
Nodal status N0 (Pw ¼ 0) N1 (P ¼ 1–3) N2 (P ¼ 4–9) N3 (P410)
94 36 12 10
61.8 23.7 7.9 6.6
37 40 29 14
30.8 33.3 24.2 11.7
Stage 0 I II III IVz
2 13 60 53 24
1.3 8.6 39.5 34.9 15.8
2 12 56 50
1.7 10 46.7 41.7
n Pathological staging did not include neoadjuvant chemotherapy patients (N ¼ 20) or those with metastatic disease who did not have breast surgery (N ¼ 12). w P denotes the number of lymph nodes involved. z Only clinical stage is shown for stage IV patients, as surgical intervention was not undertaken in all of them.
Discussion Poor outcome of breast cancer treatment has been associated with the following factors: age and stage at diagnosis, aggressive tumor characteristics, poor
1.1
Cumulative Relapse Free Survival
disease were alive and free of disease at the time of writing; 42 had relapsed and 13 are alive with persistent disease. The overall 5-year RFS rate was 62%. The cumulative 5-year RFS rates for stages I, II, and III were 87.5%, 71.6%, and 42.7%, respectively (Fig. 1). The 5-year OS rate was 67%. The cumulative 5year survival rates for stages I, II, III were 88%, 75%, and 59%, respectively (Fig. 2). In univariate Cox’s regression analysis, tumor size more than 5 cm and tumor differentiation grade were strong predictors of OS. In contrast, axillary lymph node status, tumor size more than 5 cm, and poor differentiation grade were predictors of RFS (Table 3). Tumor size, lymph node involvement, differentiation grade, and estrogen receptor status were tested in multivariate Cox’s regression analysis for their relationship with OS and RFS (Table 4). Tumor differentiation and involvement of 4–9 lymph nodes only retained independent prognostic significance for disease-free survival and OS, respectively.
1.0 I
0.9 0.8
II
0.7 RFS
0.6 0.5 0.4
III
0.3 0.2 0.1 0
20
40
60
80
100
Time (months) since diagnosis
Figure 1 Relapse-free survival (RFS) curves for the nonmetastatic group (N ¼ 128) and stages I, II, and III.
prognostic factors, and quality of treatment provided.16 Other important factors, such as awareness, socioeconomic status, and access to care are closely linked to advanced stage at presentation.17 The influence of these factors on the outcome of breast cancer treatment in Oman is discussed here. In Oman, women and girls are affected by breast cancer at a younger age than are their counterparts in the West. The mean age of 48.46 years at diagnosis
ARTICLE IN PRESS Treatment of breast cancer in a developing country
is a clear contrast to the older age at diagnosis (60–65 years) in industrial Western nations, but consistent with that in other developing countries, where the majority of patients are under 50 and premenopausal.1,6,8,9,12,18,19 Patients tend to present with large tumors, only 10% of the tumors being less than 2 cm in diameter, as against 50% and 42% in Western and Asian patients.1–3,16,17 In comparison, T1 tumors account for between 2.7% and 9% of breast cancers at presentation in several series from developing 1.1 1.0 I
Cumulative Survival
0.9
II
0.8 OS
0.7 0.6
III
0.5 0.4 IV
0.3 0.2 0.1 0.0 0
20
40
60
80
100
Time (months) since diagonals
Figure 2 Overall survival (OS) curves for the whole group (N ¼ 152) and stages I, II, III, and IV.
143 countries.7–9,12 More than half of these tumors were poorly differentiated and lacked estrogen and progesterone receptor expression. High histological grade and lack of receptor expression characterize a significant proportion of the breast cancers in developing countries, which suggests a more aggressive nature and influences survival.4,6,20 Breast-conserving surgery followed by radiotherapy is equivalent to modified radical mastectomy in terms of local recurrence and survival.21 However, in this study breast-conserving surgery had been performed in a relatively small proportion of patients. This may be explained by the advanced stage at presentation and the inclination of some surgeons to perform radical surgery without proper prior evaluation. Neoadjuvant chemotherapy is underutilized, and this may contribute to the very low rate of conservative surgery. Neoadjuvant chemotherapy allows more breast-conserving surgery and early inhibition of the proliferation of micrometastasis noted following surgery in murine models.22,23 It is a standard of care in the management of locally advanced breast cancer and has been shown to be followed by improved survival; it has an evolving role in early breast cancer management.24 However, only 20 of the patients reviewed for this study received neoadjuvant chemotherapy,
Table 3 Cox’s univariate analysis of overall survival for whole group (N ¼ 152) and relapse-free survival for nonmetastatic group (N ¼ 128). Variable
Age (years) r40 440 Menopausal status PrePostTumor size (cm) r5 45 Lymph node involvedn 0 1–3 4–9 Z10 Differentiation Good and moderate Poor Estrogen receptor status Positive Negative n
Overall survival
Relapse-free survival
RR (95% CI)
P-value
RR (95% CI)
P-value
0.88 (0.4–1.6) 1
0.7
0.72 (0.4–1.7) 1
0.4
1 1.27 (0.7–2.4)
0.46
1 1.2 (0.7–2.8)
0.6
1 2.0 (1.1–4)
0.03
1 2.2 (1.1–4.6)
0.03
1 1.23 (0.4–2.1) 1.64 (0.7–3.6) 1.3 (0.4–3.8)
0.5 0.55 0.52
1 3.22 (1.1–9.3) 5.83 (2.0–16.0) 8.6 (2.5–28.5)
0.03 0.001 0.001
(1.5–7.1)
1 2.87 (1.3–6.1)
0.006
0.3
1 2.04 (0.9–4.7)
0.09
1 3.35 0.002 1 1.57 (0.7–0.36)
Pathological lymph node involvement.
ARTICLE IN PRESS 144
Table 4
M. Al-Moundhri et al.
Cox’s multivariate analysis of prognostic factors of survival and relapse-free survival.
Variable
Tumor size (cm) r5 45 Lymph node involved 0 1–3 4–9 Z10 Differentiation Good and moderate Poor Estrogen receptor status Positive Negative
Overall survival
Relapse-free survival
Risk ratio
P-value
Risk ratio
P-value
1 1.4 (0.6–3.7)
0.46
1 2.2 (0.9–5.5)
0.047
1 2.7 (0.6–13.4) 2.1 (0.4–12.2) 2.3 (0.5–11.6)
0.2 0.4 0.3
1 6.5 (1.1–13.5) 10.7 (1.3–19.3) 11.6 (1.3–21.8)
0.1 0.03 0.03
1 5.3 (1.7–16.4)
0.004
1 1.9 (0.6–5.4)
0.3
1 1.8 (0.7–4.3)
0.02
1 1.7 (0.7–4.4)
0.26
or only 37.7% of all stage III patients. Similarly, adjuvant chemotherapy is also underutilized: only 60.2% of patients with a non-metastatic presentation received chemotherapy. The number of patients eligible for adjuvant chemotherapy may be higher, given the relatively young age, aggressive features of the disease, and advanced stage at presentation. High mastectomy rates and underutilization of neoadjuvant and adjuvant chemotherapy have been reported previously in other developing countries.25 This situation could be improved by the establishment of an early referral pattern with a multidisciplinary approach in these countries.26 There are wide variations between races and countries in the survival rates reported. The overall 5-year survival rate of 64% in this study is consistent with survival rates reported from other developing countries, which are lower than those reported in the West for various races.1,7,8,27 Two large American studies recently revealed 5-year survival rates in Asian, Hispanic, African, and white American women of 86%, 87%, 77%, and 88%, respectively.16,17 The advanced stage at presentation explains some of the survival pattern differences between races and countries: the risk of death from breast cancer for patients diagnosed in stages II and III is 2–4 times that for patients diagnosed in stage I,16 and for those diagnosed in stage IV it is nearly 14 times that following diagnosis in stage I. Stages III and IV were found in around 50% of our patients, as opposed to 11% and 18% in white and black Americans, respectively.16,17 The late presentation is due to cultural and social issues, coupled with a lack of screening programs and low awareness about breast cancer, which need to be addressed.25
Tumor size, axillary lymph node status, and tumor differentiation grade were strong predictors of RFS in univariate analysis, with axillary lymph node status retaining significance in multivariate analysis. These results are consistent with known prognostic factors in breast cancer.19 However, in this study only tumor differentiation was found to be a strong predictor of survival on multivariate analysis. More events and larger numbers of patients are needed for further assessment of the significance of the other prognostic factors. In conclusion, this study from Oman reflects the status of breast cancer presentation, care, and outcome in many developing countries. It has been established that breast cancer in Oman is characterized by poor prognostic features: the patients present not only at younger ages than in the Western world and with advanced stages of disease and extensive lymph node involvement, but also with poor differentiation and lack of estrogen and progesterone receptor expression. The survival outcome is worse than in their counterparts in the West, but consistent with results from other countries in the same region. These disturbing results call for immediate steps to raise breast cancer awareness and to introduce breast cancer screening programs in developing countries.26,28 More importantly, all patients should have easy access to tertiary referral units where a multidisciplinary assessment is made on presentation. One of the aims should be more breast-conserving surgery with greater utilization of neoadjuvant chemotherapy.26 Research exploring cultural, environmental, and genetic issues should be undertaken in an attempt to provide further explanation for the clinical and pathological features described above.
ARTICLE IN PRESS Treatment of breast cancer in a developing country
References 1. Cheng SH, Tsou MH, Liu MC, et al. Unique features of breast cancer in Taiwan. Breast Cancer Res Treat 2000;63:213–23. 2. Seow A, Duffy SW, McGee MA, et al. Breast cancer in Singapore: trends in incidence 1968–1992. Int J Epidemiol 1996;25:40–5. 3. Chow LW, Ting AC, Cheung KL, et al. Current status of breast cancer in Hong Kong. Chin Med J (Engl) 1997;110:474–8. 4. Ikpatt OF, Kuopio T, Collan Y. Proliferation in African breast cancer. Biology and prognostication in Nigerian breast cancer material. Mod Pathol 2002;15:783–9. 5. Jin F, Devesa SS, Chow WH, et al. Cancer incidence trends in urban Shanghai, 1972–1994: an update. Int J Cancer 1999;83:435–40. 6. Malik IA. Clinico-pathological features of breast cancer in Pakistan. J Pak Med Assoc 2002;52:100–4. 7. Ibrahim EM, al-Mulhim FA a-AA, al-Muhanna FA, et al. Breast cancer in the eastern province of Saudi Arabia. Med Oncol 1998;15:241–7. 8. Fakhro AE, Fateha BE, Al-Asheeri N, et al. Breast cancer. Patient characteristics and survival analysis at Salmaniya Medical Complex, Bahrain. East Medit Health J 1999;5:430–9. 9. Ezzat AA, Ibrahim EM, Raja MA, et al. Locally advanced breast cancer in Saudi Arabia: high frequency of stage iii in a young population. Med Oncol 1999;16:95–103. 10. Tabar L, Yen MF, Vitak B, et al. Mammography service screening and mortality in breast cancer patients: 20-year follow-up before and after introduction of screening. Lancet 2003;361:1405–10. 11. Jatoi I, Miller AB. Why is breast-cancer mortality declining? Lancet Oncol 2003;4:251–4. 12. Maalej M, Frikha H, Ben Salem S, et al. Breast cancer in Tunisia: clinical and epidemiological study. Bull Cancer 1999;86:302–6. 13. Al-Lawati JA, Mohammed S-KC, et al. Cancer incidence in Oman. East Medit Health J 1999;5:1035–41. 14. Ministry of Health of the Sultanate of Oman. Cancer incidence in Oman, vol. 15. Muscat: Ministry of Health; 2001. p. 28–31. 15. Greene FL, Balch CM, Fleming ID, et al. Breast cancer. AJCC Cancer staging manual, 6th ed. Heidelberg: Springer; 2002. p. 220–4.
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16. O’Malley CD, Le GM, Glaser SL, et al. Socioeconomic status and breast carcinoma survival in four racial/ethnic groups: a population-based study. Cancer 2003;97:1303–11. 17. Chu KC, Lamar CA, Freeman HP. Racial disparities in breast carcinoma survival rates. Separating factors that affect diagnosis from factors that affect treatment. Cancer 2003;97:2853–60. 18. Ezzat A, Raja MA, Zwaan F, et al. The lack of age as a significant prognostic factor in non-metastatic breast cancer. Eur J Surg Oncol 1998;24:23–7. 19. Garbay JR, Hacene K, Tubiana-Hulin M, et al. The factors in clinics’ prediction in the cancer of the breast. Retrospective study of 5 609 cases. Bull Cancer 1994;81:1078–83. 20. Aaltomaa S, Lipponen P, Eskelinen M, et al. Mitotic indexes as prognostic predictors in female breast cancer. J Cancer Res Clin Oncol 1992;118:75–81. 21. Fisher B, Anderson S, Redmond CK, et al. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995;333:1456–61. 22. Shannon C, Smith IE. Is there still a role for neoadjuvant therapy in breast cancer? Crit Rev Oncol Hematol 2003;45:77–90. 23. Fisher B, Saffer E, Rudock C, et al. Effect of local or systemic treatment prior to primary tumour removal on the production and response to a serum growth-stimulating factor. Cancer Res 1989;49:2002–4. 24. Hortobagyi GN, Ames FC, Buzdar AU, et al. Management of stage III primary breast cancer with primary chemotherapy, surgery and radiation therapy. Cancer 1988;62:2507–11. 25. Sandelin K, Apffelstaedt JP, Abdullah H, et al. Breast cancer in developing countries (Breast surgery international). Scand J Surg 2002;91:222–6. 26. Anderson BO, Braun S, Carlson RW, et al. Overview of breast health care guidelines for countries with limited resources. Breast J 2003;9(Suppl 2):S42. 27. Gajalakshmi CK. A Population-based survival study on female breast cancer in Madras, India. Br J Cancer 1997;75:771–5. 28. Knoll SM. Breast Cancer screening, a comprehensive breast cancer program in Saudi Arabia. Ann Saudi Med 1997;17: 1–3.
THE
BREAST www.elsevier.com/locate/breast
ORIGINAL ARTICLE
The outcome of treatment of breast cancer in a developing countryFOman M. Al-Moundhri*, B. Al-Bahrani, I. Pervez, S.S. Ganguly, V. Nirmala, A. Al-Madhani, K. Al-Mawaly, C. Grant Medical Oncology Branch, Department of Medicine, College of Medicine, Sultan Qaboos University, P.O. Box 35, Al-Khod, PC 123, Sultanate of Oman
KEYWORDS Breast cancer; Oman; Developing country
Summary The aim of the present study was to evaluate the outcome of treatment of breast cancer in Oman with an analysis of clinico-pathological features, treatment modalities utilized, and prognostic factors. One hundred fifty-two breast cancer patients diagnosed between January 1996 and June 2002 were evaluated retrospectively. Their mean age was 48.5 (S.D.710.8) years, and 48% of the female patients were premenopausal. The mean tumor size according to pathology was 4.6 (S.D. 3.29) cm, and 34.9% and 15.8% of patients had stage III or IV disease, respectively. Only 26.3% of the patients had breast-conserving surgery, and neoadjuvant chemotherapy was underutilized. The overall 5-year relapse-free survival (RFS) and overall (OS) survival rates were 62% and 64%, respectively. On multivariate analysis, axillary lymph node involvement and tumor differentiation were predictive of RFS and OS, respectively. Thus, breast cancer patients in Oman present with advanced stages of the disease at younger ages than their counterparts in the West and have lower survival rates. Increasing awareness and the introduction of screening programs and of a multidisciplinary approach are essential in Oman and other developing countries to improve the outcome of treatment. & 2003 Elsevier Ltd. All rights reserved.
Introduction Breast cancer is the most common cancer in women throughout the world and remains a major health problem. The incidence and clinico-pathological features of breast cancer differ between the developing countries in Asia and Africa and Western industrialized countries. The incidence of breast *Corresponding author. Tel.: þ 968-9437301; fax: þ 968513419. E-mail address: [email protected] (M. Al-Moundhri).
cancer is relatively low in developing countries compared with Western nations; however, an increase in incidence has been observed.1–3 In Asia and Africa, breast cancer affects more younger women and girls than in the West and is often in advanced stages with aggressive behavior when the patients first present.4–9 Abundant data on the outcome of breast cancer treatment are available from industrialized countries, where the use of screening mammography and the refinement of treatment have resulted in a reduction in mortality.10,11 There are numerous study reports
0960-9776/$ - see front matter & 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2003.10.001
ARTICLE IN PRESS 140
describing the clinico-pathological features of breast cancer in developing countries; however, reports on outcome of treatment remain rare, especially from Arab countries.7–9,12 The Sultanate of Oman is a developing Asian Arabic country where breast cancer is the most common female cancer. It accounts for one of every five cancers detected in female subjects, with an age-standardized incidence rate of 15.6 per 100,000 of the Omani female population.13,14 As in many other developing countries, awareness is low, cultural barriers are strong, access to specialized units is late, and there are no early breast cancer detection programs in place, although upto-date treatment modalities are applied. The aim of this study was to report on the outcome of breast cancer treatment in Oman by analyzing the clinical and pathological features, the treatment modalities utilized, prognostic factors, and survival. These variables are compared and contrasted with those recorded in other developing and developed countries.
Patients and methods This retrospective study was based on retrieval of cases diagnosed with invasive breast cancer from the computerized hospital information system of the two main teaching hospitals in the Sultanate of Oman: Sultan Qaboos University Hospital and the Royal Hospital. The oncology units of the two hospitals are the only centers in the country to which patients with a suspected or confirmed diagnosis of cancer are referred for review and further management. The majority of the study cases were diagnosed and treated in the two hospitals, while a few were operated on elsewhere and subsequently referred. Thus, surgeons in the peripheral hospitals undertake the initial intervention independently. The histopathological data of all confirmed specimens were reviewed in the two teaching hospitals to ensure consistency of histopathological reporting. All staging investigations were also performed in the two hospitals, and in the majority of cases these included chest X-ray, CT scans of chest and abdomen, and bone scan because of the advanced stage at presentation. The medical and pathological records of all patients with confirmed diagnoses of invasive breast cancer in the period between January 1996 and June 2002 were reviewed, and a database was created. The variables included were: age, sex, date of diagnosis, menstrual status, right or left breast involvement, histopathological type, clinical
M. Al-Moundhri et al.
and pathological size of the tumor, clinical and pathological skin or nipple involvement, clinical axillary lymph nodes involvement, number of lymph node removed and pathologic involvement, tumor differentiation, estrogen and progesterone receptor expression, and clinical and pathological stage at presentation. The staging was carried out using the AJCC (TNM) Cancer Staging Manual.15 The surgical intervention (mastectomy vs. lumpectomy) and the use of chemotherapy (adjuvant or neoadjuvant) and of hormonal and radiotherapy treatments were determined, and noted. The length of follow-up, the date of any relapse, and the date of death, where applicable, were also obtained from the patients’ records. Overall survival (OS) time was measured from diagnosis to death, censored by the end of followup. Relapse-free survival (RFS) time was measured from diagnosis to relapse, censored by the end of follow-up. Deaths during follow-up from causes other than breast cancer were censored. Survival and relapse estimates were obtained and presented graphically using a Kaplan–Meier test, and comparisons were made using the log-rank test. The risk ratio was estimated with a univariate setup using Cox’s proportional hazard model for the following variables: age, menopausal status, primary tumor size, axillary lymph node status, tumor differentiation, and estrogen receptor status. The statistically significant factors in univariate analysis were tested with a multivariate setup using Cox’s model. All P-values reported are nominal two-sided values. The SigmaStat SigmaPlot-10 statistical analysis software was used for the data analysis.
Results Clinical and pathological features Table 1 summarizes the clinical variables and treatment modalities utilized in 152 patients diagnosed with invasive breast cancer and treated in the study period. The mean age of all patients was 48.5 (S.D.710.8) years; 48% of the female patients were premenopausal; 20.4% were 40 years of age or younger. The majority of patients (65.8%) underwent non-breast-conserving surgery with modified radical mastectomy. Neoadjuvant chemotherapy was administered to 20 patients (13.2%), who made up only 37.7% of the 53 patients with locally advanced disease. Adjuvant external-beam radiotherapy to the breast area was administered to 96 patients (63.1%). The radiotherapy was administered in
ARTICLE IN PRESS Treatment of breast cancer in a developing country
Table 1
141
Clinical variables and management of 152 patients with invasive breast cancer.
Clinical characteristics Gender Female Male Age r40 41–50 51–60 Z60 Menstrual status (Women) Premenopausal Postmenopausal Site of breast lesion Left Right Bilateral Surgery Modified radical mastectomy Lumpectomy and axillary lymph node dissection Lumpectomy or biopsy only Chemotherapyn Neoadjuvant (All received anthracycline (AC/FEC/FAC) regimens) Adjuvant Anthracycline (AC/FEC/FAC) regimens Anthracycline-like regimen (CNF) CMF AC-T T and H Radiotherapy Hormonal treatment Tamoxifen Goserelin
Number
Percentage
150 2
98.7 1.3
31 46 49 26
20.4 30.3 32.2 17.1
72 78
48 52
74 76 2
48.7 50 1.3
100 40 12
65.8 26.3 7.9
20 65 (17) 44 (13) 7 10 (3) 4 0 (1) 96 115 98 (14) 3
13.2 42.8 (11.2)
63.1 75.7 64.4 (9.3) 2
The numbers in brackets refer to patients with metastatic disease treated with chemotherapy and/or hormonal treatment. n A ¼ Adriamycin, C ¼ cyclophosphamide, E ¼ epirubicin, F ¼ 5-fluorouracil, H ¼ Herceptin, M ¼ mitoxantrone, M ¼ methotrexate, T ¼ taxol.
various other countries, as there are no radiotherapy facilities at all in Oman. The clinical and pathological staging is summarized in Table 2. The average clinical and pathological sizes of breast tumors were 5.4 cm (S.D. 3.86) and 4.6 cm (S.D. 3.29), respectively. Clinically, T3 and T4 lesions were found in 38 (25%) and 26 patients (17%), respectively, and only 22 (14.5%) patients had T1 lesions. Axillary lymph node dissection was performed in 120 patients (excluding neoadjuvant chemotherapy patients) and 33.3%, 24.2%, and 11.7% had 1–3, 4–9, and 10 or more positive nodes, respectively. Advanced breast cancer predominated with stages III and IV being present in 53 (34.9%) and 24 (15.8%) of the patients, respectively. Stage III was found to be still more frequent on pathological staging, being found in 41.7% of the patients who underwent
surgery. The histopathological sub-types of the tumors were as follows: ductal (134), lobular (10), medullary (5), mucinous (2), and tubular (1). The differentiation was scored as high, moderate, and poor in 54 (35.5%), 25 (16.4%), and 73 (48.1%) of the tumors, respectively. The receptor status was available for 107 patients (68%), and 62 (58%) and 57 (53.3%) of these expressed estrogen and progesterone receptors, respectively.
Analysis of survival and prognostic factors With a mean follow-up interval of 35.6 months, there were 37 deaths and six patients were lost to follow-up. There were 23 deaths in the nonmetastatic group and 14 in the metastatic group. Eighty-six of the 128 patients with non-metastatic
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Table 2
M. Al-Moundhri et al.
Clinical and pathological staging of patients with invasive breast cancer. Clinical stage (N ¼ 152)
Pathological stagen (N ¼ 120)
Number
Percentage
Number
Percentage
Primary tumor Tis T1 T2 T3 T4
2 22 64 38 26
1.3 14.5 42.1 25 17.1
2 12 66 32 8
1.7 10 55 26.7 6.6
Nodal status N0 (Pw ¼ 0) N1 (P ¼ 1–3) N2 (P ¼ 4–9) N3 (P410)
94 36 12 10
61.8 23.7 7.9 6.6
37 40 29 14
30.8 33.3 24.2 11.7
Stage 0 I II III IVz
2 13 60 53 24
1.3 8.6 39.5 34.9 15.8
2 12 56 50
1.7 10 46.7 41.7
n Pathological staging did not include neoadjuvant chemotherapy patients (N ¼ 20) or those with metastatic disease who did not have breast surgery (N ¼ 12). w P denotes the number of lymph nodes involved. z Only clinical stage is shown for stage IV patients, as surgical intervention was not undertaken in all of them.
Discussion Poor outcome of breast cancer treatment has been associated with the following factors: age and stage at diagnosis, aggressive tumor characteristics, poor
1.1
Cumulative Relapse Free Survival
disease were alive and free of disease at the time of writing; 42 had relapsed and 13 are alive with persistent disease. The overall 5-year RFS rate was 62%. The cumulative 5-year RFS rates for stages I, II, and III were 87.5%, 71.6%, and 42.7%, respectively (Fig. 1). The 5-year OS rate was 67%. The cumulative 5year survival rates for stages I, II, III were 88%, 75%, and 59%, respectively (Fig. 2). In univariate Cox’s regression analysis, tumor size more than 5 cm and tumor differentiation grade were strong predictors of OS. In contrast, axillary lymph node status, tumor size more than 5 cm, and poor differentiation grade were predictors of RFS (Table 3). Tumor size, lymph node involvement, differentiation grade, and estrogen receptor status were tested in multivariate Cox’s regression analysis for their relationship with OS and RFS (Table 4). Tumor differentiation and involvement of 4–9 lymph nodes only retained independent prognostic significance for disease-free survival and OS, respectively.
1.0 I
0.9 0.8
II
0.7 RFS
0.6 0.5 0.4
III
0.3 0.2 0.1 0
20
40
60
80
100
Time (months) since diagnosis
Figure 1 Relapse-free survival (RFS) curves for the nonmetastatic group (N ¼ 128) and stages I, II, and III.
prognostic factors, and quality of treatment provided.16 Other important factors, such as awareness, socioeconomic status, and access to care are closely linked to advanced stage at presentation.17 The influence of these factors on the outcome of breast cancer treatment in Oman is discussed here. In Oman, women and girls are affected by breast cancer at a younger age than are their counterparts in the West. The mean age of 48.46 years at diagnosis
ARTICLE IN PRESS Treatment of breast cancer in a developing country
is a clear contrast to the older age at diagnosis (60–65 years) in industrial Western nations, but consistent with that in other developing countries, where the majority of patients are under 50 and premenopausal.1,6,8,9,12,18,19 Patients tend to present with large tumors, only 10% of the tumors being less than 2 cm in diameter, as against 50% and 42% in Western and Asian patients.1–3,16,17 In comparison, T1 tumors account for between 2.7% and 9% of breast cancers at presentation in several series from developing 1.1 1.0 I
Cumulative Survival
0.9
II
0.8 OS
0.7 0.6
III
0.5 0.4 IV
0.3 0.2 0.1 0.0 0
20
40
60
80
100
Time (months) since diagonals
Figure 2 Overall survival (OS) curves for the whole group (N ¼ 152) and stages I, II, III, and IV.
143 countries.7–9,12 More than half of these tumors were poorly differentiated and lacked estrogen and progesterone receptor expression. High histological grade and lack of receptor expression characterize a significant proportion of the breast cancers in developing countries, which suggests a more aggressive nature and influences survival.4,6,20 Breast-conserving surgery followed by radiotherapy is equivalent to modified radical mastectomy in terms of local recurrence and survival.21 However, in this study breast-conserving surgery had been performed in a relatively small proportion of patients. This may be explained by the advanced stage at presentation and the inclination of some surgeons to perform radical surgery without proper prior evaluation. Neoadjuvant chemotherapy is underutilized, and this may contribute to the very low rate of conservative surgery. Neoadjuvant chemotherapy allows more breast-conserving surgery and early inhibition of the proliferation of micrometastasis noted following surgery in murine models.22,23 It is a standard of care in the management of locally advanced breast cancer and has been shown to be followed by improved survival; it has an evolving role in early breast cancer management.24 However, only 20 of the patients reviewed for this study received neoadjuvant chemotherapy,
Table 3 Cox’s univariate analysis of overall survival for whole group (N ¼ 152) and relapse-free survival for nonmetastatic group (N ¼ 128). Variable
Age (years) r40 440 Menopausal status PrePostTumor size (cm) r5 45 Lymph node involvedn 0 1–3 4–9 Z10 Differentiation Good and moderate Poor Estrogen receptor status Positive Negative n
Overall survival
Relapse-free survival
RR (95% CI)
P-value
RR (95% CI)
P-value
0.88 (0.4–1.6) 1
0.7
0.72 (0.4–1.7) 1
0.4
1 1.27 (0.7–2.4)
0.46
1 1.2 (0.7–2.8)
0.6
1 2.0 (1.1–4)
0.03
1 2.2 (1.1–4.6)
0.03
1 1.23 (0.4–2.1) 1.64 (0.7–3.6) 1.3 (0.4–3.8)
0.5 0.55 0.52
1 3.22 (1.1–9.3) 5.83 (2.0–16.0) 8.6 (2.5–28.5)
0.03 0.001 0.001
(1.5–7.1)
1 2.87 (1.3–6.1)
0.006
0.3
1 2.04 (0.9–4.7)
0.09
1 3.35 0.002 1 1.57 (0.7–0.36)
Pathological lymph node involvement.
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Table 4
M. Al-Moundhri et al.
Cox’s multivariate analysis of prognostic factors of survival and relapse-free survival.
Variable
Tumor size (cm) r5 45 Lymph node involved 0 1–3 4–9 Z10 Differentiation Good and moderate Poor Estrogen receptor status Positive Negative
Overall survival
Relapse-free survival
Risk ratio
P-value
Risk ratio
P-value
1 1.4 (0.6–3.7)
0.46
1 2.2 (0.9–5.5)
0.047
1 2.7 (0.6–13.4) 2.1 (0.4–12.2) 2.3 (0.5–11.6)
0.2 0.4 0.3
1 6.5 (1.1–13.5) 10.7 (1.3–19.3) 11.6 (1.3–21.8)
0.1 0.03 0.03
1 5.3 (1.7–16.4)
0.004
1 1.9 (0.6–5.4)
0.3
1 1.8 (0.7–4.3)
0.02
1 1.7 (0.7–4.4)
0.26
or only 37.7% of all stage III patients. Similarly, adjuvant chemotherapy is also underutilized: only 60.2% of patients with a non-metastatic presentation received chemotherapy. The number of patients eligible for adjuvant chemotherapy may be higher, given the relatively young age, aggressive features of the disease, and advanced stage at presentation. High mastectomy rates and underutilization of neoadjuvant and adjuvant chemotherapy have been reported previously in other developing countries.25 This situation could be improved by the establishment of an early referral pattern with a multidisciplinary approach in these countries.26 There are wide variations between races and countries in the survival rates reported. The overall 5-year survival rate of 64% in this study is consistent with survival rates reported from other developing countries, which are lower than those reported in the West for various races.1,7,8,27 Two large American studies recently revealed 5-year survival rates in Asian, Hispanic, African, and white American women of 86%, 87%, 77%, and 88%, respectively.16,17 The advanced stage at presentation explains some of the survival pattern differences between races and countries: the risk of death from breast cancer for patients diagnosed in stages II and III is 2–4 times that for patients diagnosed in stage I,16 and for those diagnosed in stage IV it is nearly 14 times that following diagnosis in stage I. Stages III and IV were found in around 50% of our patients, as opposed to 11% and 18% in white and black Americans, respectively.16,17 The late presentation is due to cultural and social issues, coupled with a lack of screening programs and low awareness about breast cancer, which need to be addressed.25
Tumor size, axillary lymph node status, and tumor differentiation grade were strong predictors of RFS in univariate analysis, with axillary lymph node status retaining significance in multivariate analysis. These results are consistent with known prognostic factors in breast cancer.19 However, in this study only tumor differentiation was found to be a strong predictor of survival on multivariate analysis. More events and larger numbers of patients are needed for further assessment of the significance of the other prognostic factors. In conclusion, this study from Oman reflects the status of breast cancer presentation, care, and outcome in many developing countries. It has been established that breast cancer in Oman is characterized by poor prognostic features: the patients present not only at younger ages than in the Western world and with advanced stages of disease and extensive lymph node involvement, but also with poor differentiation and lack of estrogen and progesterone receptor expression. The survival outcome is worse than in their counterparts in the West, but consistent with results from other countries in the same region. These disturbing results call for immediate steps to raise breast cancer awareness and to introduce breast cancer screening programs in developing countries.26,28 More importantly, all patients should have easy access to tertiary referral units where a multidisciplinary assessment is made on presentation. One of the aims should be more breast-conserving surgery with greater utilization of neoadjuvant chemotherapy.26 Research exploring cultural, environmental, and genetic issues should be undertaken in an attempt to provide further explanation for the clinical and pathological features described above.
ARTICLE IN PRESS Treatment of breast cancer in a developing country
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