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© 1999 American Society for Clinical Oncology Prognostic and Predictive Factors for Patients With Metastatic Breast Cancer Undergoing Aggressive Induction Therapy Followed by High-Dose Chemotherapy With Autologous Stem-Cell SupportFrom the Duke University Medical Center Marrow and Stem Cell Transplantation Program, Durham, NC. Address reprint requests to David A. Rizzieri, MD, Division of Oncology and Bone Marrow Transplantation, Box 3961, Duke University Medical Center, Durham, NC 27710; email rizzi003{at}mc.duke.edu
PURPOSE: We performed a retrospective review to determine predictive and prognostic factors in patients with metastatic breast cancer who received induction therapy, and, if they responded to treatment, high-dose chemotherapy. PATIENTS AND METHODS: Patients with metastatic breast cancer received induction therapy with doxorubicin, fluorouracil, and methotrexate (AFM). Partial responders then received immediate high-dose chemotherapy, whereas those who achieved complete remission were randomized to immediate or delayed high-dose chemotherapy with hematopoietic stem-cell support. We performed a retrospective review of data from these patients and used Cox proportional hazards regression models for analyses.
RESULTS: The overall response rate for the 425 patients enrolled was 74% (95% confidence interval, 70% to 78%). Multivariate analysis of data from all 425 patients revealed that positive estrogen receptor status (P = .0041), smaller metastatic foci ( CONCLUSION: The chance for long-term remission with induction therapy with AFM and high-dose chemotherapy is increased for hormone receptor positive–patients with nonvisceral metastases who have not received prior adjuvant chemotherapy and have long disease-free intervals.
BREAST CANCER REMAINS the most common malignancy of women in the United States, with an estimated 180,200 new cases annually, and 17% of cancer deaths among women are breast cancer related.1 Although overall breast cancer mortality has decreased slightly over the last 10 years, the outlook for those with metastatic disease is dismal; only 5% of these women survive for 5 years when treated with current standard chemotherapy.2,3 Novel therapies, including high-dose chemotherapy with bone marrow or stem-cell support, have been evaluated as treatments for patients with metastatic disease. We reported the results of an early-phase study involving patients with metastatic disease who received aggressive induction therapy with doxorubicin, fluorouracil, and methotrexate (AFM), followed by high-dose therapy.4 With a median length of follow-up of 20 months, the disease-free survival rate was 22%.4 The early encouraging results led us and others to conduct randomized trials. In a randomized, prospective trial involving patients with metastatic breast cancer, Bezwoda et al5,6 compared a standard chemotherapy approach with high-dose chemotherapy plus autologous bone marrow transplantation. Twenty percent of study patients who received high-dose chemotherapy remained in remission for more than 3 years (median survival time, 90 weeks), whereas there were no long-term survivors among those treated with standard therapy (median survival time, 45 weeks) (P  .01). We have completed a randomized, prospective trial in which the proper timing of high-dose therapy in patients with metastatic disease was addressed. Patients having a complete response to induction with the AFM regimen were randomized to undergo immediate transplantation or delayed transplantation. Preliminary results revealed a statistically significant improvement in progression-free survival time for the group that underwent immediate transplantation (13 v 4 months). However, the median overall survival time was 20 months for the group that underwent immediate transplantation and 38 months for those who were observed and had high-dose therapy delayed until the time of progression.7 Long-term follow-up data are being analyzed separately. The purpose of the current retrospective review was to identify factors predictive of response to induction therapy with AFM and prognostic factors predictive of long-term survival. These factors may enable us to identify subgroups of patients who will do particularly well, or poorly, when treated with aggressive chemotherapy requiring bone marrow transplantation. In addition to targeting therapies more appropriately, the goal is to select patients who may benefit from specific interventions.
Patient Eligibility and Evaluation Four hundred twenty-five patients with metastatic or inflammatory breast cancer were enrolled between 1987 and 1995 onto our single-institution, randomized trial. Currently, the median length of follow-up is 6 years (range, 2 to 10 years). To be eligible, all hormone receptor–positive patients, except those with inflammatory disease, had to have failed one regimen of hormonal therapy. Patients were required not to have received prior chemotherapy for inoperable or metastatic disease, and the prior total doxorubicin dose in the adjuvant setting had to have been less than 280 mg/m2. Measurable disease had to be present outside an irradiated field or to have developed within an irradiated field after radiotherapy. Metastatic bone lesions alone were not considered measurable disease, and patients with bone-only metastases were treated according to a separate protocol. The trial protocol was approved by our local institutional review board, and all patients provided informed consent.
All patients underwent staging computed tomography of the head, chest, abdomen, and pelvis; bone scintigraphy; electrocardiography; multiple gated acquisition scanning; pulmonary function tests; urinalysis; creatinine clearance evaluation; bilateral bone marrow biopsies; and renal and liver function tests. Each patient was required to have a performance status of 0 or 1 (Cancer and Leukemia Group B [CALGB] toxicity criteria), no more than three areas of bony disease, no pelvic bone involvement, and a biopsy specimen for pathologic confirmation of metastatic breast cancer reviewed at our institution. Also required were adequate lung function with forced vital capacity, forced expiratory volume, and diffusion capacity of
Induction Chemotherapy If the nadir WBC count was less than 1,000/L or the mucositis greater than grade 3 (CALGB criteria), the doxorubicin dose for the subsequent cycle was decreased by 2.5 mg/m2. If the mucositis was greater than grade 2, the daily fluorouracil dose was decreased by 250 mg/m2/d for the subsequent cycles. If it was time for the subsequent cycle of chemotherapy and the WBC count was less than 3,000/L, the platelet count was less than 75,000/L, or mucositis greater than grade 1 (CALGB criteria) was still present, chemotherapy was delayed and the patient was followed twice weekly, with therapy instituted within 48 hours of documented recovery in terms of these parameters. In an attempt to maximize the number of complete responders to treatment, if an area of disease remained that could not be surgically excised, radiation therapy at a dose likely to produce local control (usually in the range of 40 to 50 Gy) was used before final diagnostic staging was performed. Radiation was delivered to the identified tumor, with a small margin included to ensure that the tumor was adequately encompassed by the beam. Patients who had a complete response to the AFM induction regimen with or without radiotherapy and/or surgery were randomized to receive high-dose combination therapy with cyclophosphamide, cisplatin, and carmustine followed by hematopoietic stem-cell support as immediate consolidation or at the time of relapse (Fig 1). Patients randomized to the delayed-transplantation arm were followed at 4- to 6-week intervals and their disease was restaged every 12 weeks with the use of bone scintigraphy and computed tomography of the chest, abdomen, and pelvis. Patients who responded but did not achieve a complete response received immediate high-dose chemotherapy with hematopoietic support.
Preparatory Regimen
Response
Statistics
A model using logistic regression analysis was developed to allow us to predict, a priori, the chance for a patient with metastatic disease responding to induction therapy with AFM.
Outcomes After AFM induction chemotherapy, 113 patients had a complete response and 202 a partial response, an overall response rate of 74% (315 of 425; 95% confidence interval [CI], 70% to 78%). Seven patients who attained complete remission refused to undergo transplantation, and six had inflammatory disease and a clinical complete response but a pathologic partial response and therefore were offered immediate transplantation and not randomized. One hundred of the 113 patients who achieved a complete response were randomized to immediate or delayed high-dose chemotherapy with autologous support; 51 were randomized to the delayed-transplantation arm. Of the 202 with a partial response, two refused to receive high-dose chemotherapy and seven were denied coverage by insurance companies. Thus, 299 of all 425 enrolled patients actually proceeded to the high-dose chemotherapy phase of the protocol and survival was studied in all 425 patients. At the completion of therapy, 40% of all patients (171 of 425; 95% CI, 36% to 45%) and 58% of patients who received high-dose chemotherapy (171 of 299) had attained a complete response. For the whole group of 425 patients, the 5-year overall survival rate was 18% (95% CI, 12% to 25%) and the progression-free survival rate was 11% (95% CI, 7% to 17%). The 5-year survival rate for patients with stable or progressive disease after treatment with AFM (83 of 425) was 5%, and 27 patients were not assessable for response to AFM therapy. At the time of this analysis, 114 of the 425 patients remained alive, 63 of them progression-free. Among the patients with a complete or partial response to AFM therapy (315), the 1-year survival rate was 77% for the 299 transplant recipients and 54% for the 16 who did not undergo transplantation. Of all patients who responded to AFM therapy and underwent immediate transplantation (49 in complete remission and 199 with a partial response), 16% (50 patients) (95% CI, 10% to 26%) remained progression-free at 5 years, and the overall survival rate was 20% (95% CI, 12% to 32%). Of the 199 patients with a partial response who then received high-dose therapy, 58 achieved a complete response (29%), and the long-term remission rate and survival for these 58 patients were not different from those for the patients who began receiving high-dose therapy in complete remission. With regard to patients who underwent immediate high-dose chemotherapy and attained complete remission by the completion of therapy, when the Kaplan-Meier method was used, 28% were alive and disease-free at 5 years, with a 38% overall survival rate (95% CI, 21% to 59%). Those with only a partial response to high-dose chemotherapy had a 5-year survival rate of 11%.
Prognostic Factors
Cox proportional hazards multivariate regression analysis revealed several prognostic signs related to improved survival for all 425 patients (Table 6), including positive estrogen receptor status (P = .0041, RR = 0.654), smaller metastatic foci (P = .0165, RR = 1.045), longer disease-free interval from initial diagnosis to diagnosis of metastases (P = .0051, RR = 0.825), and prior use of adjuvant tamoxifen (P = .0152, RR = 0.680). Both estrogen receptor status and use of tamoxifen, although correlated (Spearman correlation = 0.38, P = .0001), remain significant in the multivariate model. With multivariate modeling, worse outcome was noted with the prior use of adjuvant chemotherapy (P = .0001, RR = 2.124), particularly if that therapy included doxorubicin (P = .0038), and the presence of visceral disease, especially for those with liver involvement (P = .0001, RR = 1.705). The values relating to improved progression-free survival are similar to those noted for overall survival (Table 6).
Important differences can be seen, however, when these results for all 425 patients are compared with the univariate results for the 299 patients who achieved a complete or partial response and underwent transplantation. In this group of patients who had already demonstrated responsiveness to chemotherapy (AFM induction therapy), fewer factors proved to have prognostic importance for overall or progression-free survival (factors are indicated by an asterisk in Table 5). In this subgroup, we specifically attempted to identify factors that relate to prognosis after transplantation. Therefore, a landmark analysis was performed, with overall and progression-free survival starting at the time of transplantation, which allowed us to control for possible lead-time bias in the events before the actual transplantation. Patients who had received prior adjuvant chemotherapy did worse (P = .02, RR = 1.461), although prior doxorubicin treatment did not adversely affect this group (P = .62). Those with visceral metastases fared worse (P = .013, RR = 1.484), with liver involvement again accounting for the majority of the significance noted (P = .002, RR = 1.589). When multivariate analysis of data from this group of responders was performed, fewer prognostic variables were identified as important (Table 6). Again, those with visceral disease, particularly liver metastases (P = .0006, RR = 1.68), did worse. Those who had not received prior adjuvant therapy (P = .0023, RR = 1.65) and those who had received prior adjuvant tamoxifen therapy (P = .0143, RR = 0.645) had better overall survival. The significant detrimental effect of having visceral disease is shown in Fig 2. Those with nonvisceral metastases had a median survival of 2.25 years, compared with 1.82 years for those with lung metastases only, 1.65 years for those with liver involvement only, and 1.26 years for those with both lung and liver involvement. Prior adjuvant therapy with tamoxifen was the only factor that related to improved progression-free survival (P = .047, RR = 0.74) in this subgroup of 299 responders.
Among those with liver metastases, 22 of 89 patients followed for more than 2 years remained progression-free and 14 of 52 followed for more than 3 years remained progression-free. Among those with
Thirty-nine (8%) of all 425 patients were long-term (
Predictive Factors
The median age of our patients at the time of diagnosis was lower than that of most patients with metastatic breast cancer, and many of our patients were premenopausal, unlike most patients with the disease. These differences may indicate a bias on the part of physicians with regard to the choice of patients for referral. At the time of initial diagnosis in the patients in our study, there was a wide range of tumor sizes (45 patients had inflammatory disease), degrees of nodal involvement, and hormone receptor levels. Initial therapies also differed significantly in terms of surgery and use of adjuvant radiotherapy, chemotherapy, and hormonal therapy. At the time metastatic disease was diagnosed, there was a wide variety of sites of involvement and levels of tumor burden, with 66 patients with involvement of  three sites and 50 patients with both liver and lung metastases. These factors, coupled with the large number of patients studied, have allowed us to outline a model for response to AFM therapy, and thus for possible long-term survival, among patients with metastatic breast cancer. Our data (Table 7) can be used to predict a priori who may respond well, or poorly, to this therapy. Using univariate analysis, we identified multiple variables relating to progression-free and overall survival for all 425 patients with metastatic breast cancer who underwent this aggressive treatment (Table 5). Factors of interest that did not prove to be significant included the size of the primary tumor and the number or percentage of nodes involved at the time of diagnosis. This is understandable given the fact that the study patients were required to have metastatic disease at the time of entry. Tumor histology and grade also did not prove to be significant, perhaps because the proclivity of the cancer in this group of patients to metastasize had already been shown. Better overall and progression-free survivals were noted for patients who were estrogen receptor–positive, and these survivals were better than for progesterone receptor–positive patients. Also, those with higher estrogen or progesterone receptor values did better than did those with lower receptor values, as did those who were treated with tamoxifen in the adjuvant setting. This is particularly interesting given the fact that all hormone-sensitive patients (except those with inflammatory disease) had to have disease progression after one regimen of hormonal therapy to be entered onto the trial. Further, multivariate analysis (Table 6) also showed both receptor status and prior tamoxifen therapy to be important prognostic factors. These data suggest that there are other biologically important factors that we have not identified in those who are hormone-sensitive, factors such as growth rate, glutathione S-transferase activity, or ERB2 status. The fact that those who had received prior adjuvant therapy had a significantly worse prognosis suggests that either the acquisition or selection of drug-resistant cells may be an important factor in the progression of breast cancer. This is supported by preliminary evidence from our center and others that not only are p53 alterations, commonly associated with drug resistance, found at multiple stages of breast cancer9 but detection of p53 mutations and increased glutathione S-transferase activity in the primary tumors correlates with worse outcome (unpublished data). We are evaluating the importance of these and other various potential mechanisms of resistance in this population of patients, and this may lead to the development or discovery of more effective agents or more effective methods of delivering chemotherapy.10,11 Although newer agents such as taxanes may be helpful,12,13 our review shows that any prior chemotherapy exposure is associated with worse outcome. This suggests that administration of high-dose chemotherapy early in the course of treatment may be important for optimal outcome. When a landmark analysis was used to evaluate the data from the subgroup of 299 transplant recipients, only a few of the prognostic factors found to be important by univariate analysis proved again to be important (Table 5). These patients had proven response to an aggressive doxorubicin-containing induction regimen (AFM therapy); therefore, it is not surprising that prior treatment with doxorubicin was no longer a significant prognostic factor. Hormonal status was less significant, and the use of tamoxifen in the adjuvant setting did not affect the outcome. However, liver involvement still foretold a worse outcome, although some patients with liver involvement or liver and lung involvement remained alive and disease-free in the long term (Fig 2). Findings by multivariate analysis (Table 6) for this responding subgroup suggest that once a patients proves responsive to chemotherapy, only bulky disease involvement of visceral organs, prior exposure to any chemotherapy (which may lead to increased drug resistance), and prior exposure to tamoxifen in the adjuvant setting affect outcome. This again supports the use of more aggressive measures early in the course of treatment. Although the presence of liver metastases, compared with metastases at other visceral sites, is a significant prognostic factor, this is due to a more rapid decline in survival among those with liver involvement (Fig 2) The survival rate for this subgroup of patients reached the same plateau (nearly 10%) as the rate for those with other sites of visceral involvement. The reason for this remains unclear, although it does not seem to be increased toxicity. Figure 3A shows the continued long-term improved outcome for those who received high-dose chemotherapy and did not receive prior adjuvant chemotherapy compared with those who received prior adjuvant chemotherapy. By contrast, the improved outcome for hormone receptor–positive patients wanes after 5 years (Fig 3B). Prior use of tamoxifen and a longer interval from initial diagnosis to metastasis also had a decreased effect on overall and progression-free survival after 5 years (data not shown). These findings clarify why analysis of data from the subgroup of 39 long-term disease-free responders failed to reveal any significant prognostic variables other than prior adjuvant therapy, even though factors important to overall prognosis were identified through multivariate analysis. It further suggests that some biologic aspect of the disease, as yet unidentified, may be more important than the patient's having received the drug.
Ayash et al14 reported on 62 patients with metastatic breast cancer who underwent high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin. These investigators noted that those with chemosensitive disease, fewer sites of disease, and prolonged disease-free intervals seemed to have better outcomes. They also found that whether the patient had visceral or nonvisceral disease was an important factor, as was prior chemotherapy. In that study, patients who were estrogen receptor–negative had better outcomes. This may reflect a difference in the patient populations studied; in our trial, for example, all hormone-positive patients had to have failed a regimen of hormonal therapy before being enrolled. Our results are otherwise similar, although we were able to determine that the benefit of a longer disease-free interval or positive hormonal state wanes with time. Reviewing data in the Autologous Blood and Marrow Transplant Registry, Antman et al15 found that among the 5,886 patients who received high-dose chemotherapy for breast cancer (locally advanced or metastatic), the only significant variable in the metastatic setting relating to outcome was complete response to induction therapy before autologous transplantation. The 3-year probability of progression-free survival was 13% for partial responders and 32% for complete responders. Our results show that up to 29% of those with a partial response to induction can attain a complete response after autologous transplantation, and this response is just as durable in terms of overall and progression-free survivals as the result among those who attain a complete response to induction. We studied significantly more variables in our trial than did Antman et al,15 and there may have been fewer confounding factors, given that only one treatment approach was used in our study. This may have made it possible for us to identify other important factors not noted by those investigators (size of metastatic disease, visceral involvement, and prior therapy). Variables were analyzed in two other studies, with shorter lengths of follow-up, involving patients with metastatic breast cancer who underwent high-dose chemotherapy; results were compared with results for historical control groups treated with standard chemotherapy regimens. These investigators noted, as we did, that a shorter disease-free interval, prior adjuvant therapy, the presence of liver metastases,16,17 and an increasing number of sites of metastases portend worse outcome.16 Contrary to their findings, progesterone negative status was not a significant variable in our patients, although estrogen receptor status was important, again through 5 years of follow-up. This may be due to the use of different entry criteria, different induction therapies, or alternative preparative regimens. The Stanford group18 found that the presence of visceral disease related to worse outcome in a smaller group of patients treated with high-dose chemotherapy. Our results extend these observations by showing the duration of the effect of the disease-free interval and liver involvement to be approximately 5 years. In patients undergoing less myelotoxic chemotherapy regimens that do not require hematopoietic stem-cell support, liver involvement and prior chemotherapy have also been found to be predictive of worse outcome. Further, prior hormonal therapy also has been identified as a poor prognostic factor,19 but the importance wanes with time, as it did in our patient population. This may be due to a lead-time bias; those who had previously received hormonal therapy and who remained in remission longer initially and then relapsed and did not respond to further hormonal therapy were compared with patients with metastatic breast cancer who had not previously received hormonal therapy and who had a sustained response after it was initiated. The finding that those with nonvisceral metastases have a higher chance of responding, as well as the fact that patients with smaller metastatic foci have an improved prognosis, calls into question the standard approach of follow-up postadjuvant therapy, usually termed a symptom-directed approach. It is presently accepted that detection of metastases early in the metastatic disease process has no significant effect on ultimate outcome with standard therapy; therefore, radiographic examinations are performed only at the onset of new symptoms or if physical examination findings warrant them. In contrast to this, we have shown that treatment with high-dose chemotherapy at the time disease is minimal and/or confined to nonvisceral sites results in significantly better outcome. Patients with nonvisceral metastases have a much greater chance of responding to induction therapy and being considered appropriate candidates for high-dose chemotherapy, and patients with smaller metastatic foci have a much better chance of long-term survival. This suggests that those who are candidates for more aggressive therapies at the time of metastases should have routine physical, radiographic, and laboratory examinations, rather than be treated using a symptom-directed approach. Alternatively, those with less disease may have a biologically different tumor type, one that is more amenable to therapy. Our results reveal that patients who have not been heavily pretreated may do reasonably well with an aggressive approach that includes high-dose chemotherapy, although many patients may still relapse. Recent advances since the initiation of this trial may improve these outcomes. These advances include the use of peripheral-blood stem cells and the use of growth factors, associated with faster recovery and less toxicity (treatment-related mortality was 20% in the first year and 3% in the last year of this trial). Novel approaches must be developed to manipulate minimal residual disease after transplantation, approaches such as the use of antiangiogenesis factors or dendritic cell vaccines, ex vivo expansion, or purging of the hematopoietic stem cells. Therefore, in the case of eligible patients who are interested in a medically aggressive approach, we encourage early referral to a stem-cell transplantation center where a high-dose chemotherapy approach may be used in conjunction with these novel manipulations of minimal residual disease potentially to improve long-term remission rates. In summary, those who have not received prior chemotherapy and have nonvisceral metastases have a very good chance of responding to induction therapy. Those who have nonvisceral metastases, have a long interval from initial diagnosis to diagnosis of metastasis, have not received adjuvant chemotherapy, have smaller metastatic deposits, are estrogen receptor–positive, and have received prior tamoxifen therapy in the adjuvant setting have a greater likelihood of longer survival with this approach than do patients who do not have these characteristics.
Supported in part by National Cancer Institute grant no. 5 PO1 CA47741-08. We thank our referring physicians, house staff, and nurses for their outstanding care and support of the patients and their families.
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Chu KC, Tarone RE, Kessler LG, et al: Recent trends in U.S. breast cancer incidence, survival, and mortality rates. J Natl Cancer Inst88:1571-1579, 1996 3. Greenberg PA, Hortobagyi GN, Smith TL, et al: Long term follow up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol14:2197-2205, 1996[Abstract] 4. Jones RB, Shpall EJ, Ross M, et al: AFM induction chemotherapy, followed by intensive alkylating agent consolidation with autologous bone marrow support (ABMS) for advanced breast cancer: Current results. Proc Am Soc Clin Oncol9:9, 1990 (abstr 30) 5. Bezwoda WR, Seymour L, Dansey RD: High dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: A randomized trial. J Clin Oncol13:2483-2489, 1995[Abstract] 6. Bezwoda WR: Primary high dose chemotherapy for metastatic breast cancer: Update and analysis of prognostic factors. Proc Am Soc Clin Oncol 17:115a, 1998 (abstr 445) 7. Peters WP, Jones RB, Vredenburgh JJ, et al: A large, prospective, randomized trial of high dose combination alkylating agents (CPB) with autologous cellular support (ABMS) as consolidation for patients with metastatic breast cancer achieving complete remission after intensive doxorubicin-based induction therapy (AFM). Br Cancer Res Treat37:11, 1996 (suppl 35, abstr) [Medline] 8. Cox DR: Regression models and life tables. J Royal Stat Soc B,34:187-220, 1972
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Antman KA, Rowlings PA, Vaughan WP, et al: High dose chemotherapy with autologous hematopoietic stem cell support for breast cancer in North America. J Clin Oncol15:1870-1879, 1997 16. Bociek G, Reed E, Tarantolo S, et al: A comparative study of high dose chemotherapy/stem cell transplantation (HCSCT) versus standard chemotherapy (CT) in patients (PTS) with metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 17:114a, 1998 (abstr 440) 17. Dunphy FR, Spitzer G, Fornoff JER, et al: Factors predicting long term survival for metastatic breast cancer patients treated with high dose chemotherapy and bone marrow support. Cancer73:2157-2167, 1994[Medline] 18. Hu WW, Negrin RS, Stockerl-Goldstein KE, et al: Factors associated with the outcome for patients with stage IV breast cancer undergoing high dose chemotherapy with hematopoietic cell support. Proc Am Soc Clin Oncol 16:98a, 1997 (abstr 344) 19. Berruti A, Zola P, Buniva MG, et al: Prognostic factors in metastatic breast cancer patients obtaining objective response or disease stabilization after first line chemotherapy with epirubicin: Evidence for a positive effect of maintenance hormonal therapy on overall survival. Anticancer Res17:2763-2768, 1997[Medline] Submitted November 23, 1998; accepted June 9, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test was used to determine significance. For the multivariate model, a stepwise selection method was used to select significant variables when univariately significant (P = .05) factors were given. To evaluate model fit, we used the Wald 
