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© 2000 American Society for Clinical Oncology Effect of Radiotherapy After Breast-Conserving Treatment in Women With Breast Cancer and Germline BRCA1/2 MutationsFrom the Department of Radiation Oncology, University of Michigan, and University of Michigan Cancer Center Biostatistics Core, Ann Arbor, MI; Center for Research in Women’s Health, University of Toronto, Toronto; Radiation Therapy Program, British Columbia Cancer Agency, Vancouver, Canada; Departments of Medicine, Genetics, and Radiation Oncology, University of Pennsylvania, Philadelphia, PA; Department of Radiation Oncology, University of Utah, Salt Lake City, UT; Joint Center for Radiotherapy and Dana-Farber Cancer Institute, Harvard University, Boston, MA; Department of Radiation Oncology and Division Hematology/Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC; Departments of Radiation and Cellular Oncology and Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL; and Department of Therapeutic Radiology, Yale University, New Haven, CT. Address reprint requests to Lori J. Pierce, MD, Department of Radiation Oncology, University of Michigan School of Medicine, UH-B2C490, Box 0010, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0010; email ljpierce{at}umich.edu
PURPOSE: Recent laboratory data suggest a role for BRCA1/2 in the cellular response to DNA damage. There is a paucity of clinical data, however, examining the effect of radiotherapy (RT), which causes double-strand breaks, on breast tissue from BRCA1/2 mutation carriers. Thus the goals of this study were to compare rates of radiation-associated complications, in-breast tumor recurrence, and distant relapse in women with BRCA1/2 mutations treated with breast-conserving therapy (BCT) using RT with rates observed in sporadic disease. PATIENTS AND METHODS: Seventy-one women with a BRCA1/2 mutation and stage I or II breast cancer treated with BCT were matched 1:3 with 213 women with sporadic breast cancer. Conditional logistic regression models were used to compare matched cohorts for rates of complications and recurrence. RESULTS: Tumors from women in the genetic cohort were associated with high histologic (P = .0004) and nuclear (P = .009) grade and negative estrogen (P = .0001) and progesterone (P = .002) receptors compared with tumors from the sporadic cohort. Using Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity scoring, there were no significant differences in acute or chronic morbidity in skin, subcutaneous tissue, lung, or bone. The 5-year actuarial overall survival, relapse-free survival, and rates of tumor control in the treated breast for the patients in the genetic cohort were 86%, 78%, and 98%, respectively, compared with 91%, 80%, and 96%, respectively, for the sporadic cohort (P = not significant). CONCLUSION: There was no evidence of increased radiation sensitivity or sequelae in breast tissue heterozygous for a BRCA1/2 germline mutation compared with controls, and rates of tumor control in the breast and survival were comparable between BRCA1/2 carriers and controls at 5 years. Although additional follow-up is needed, these data may help in discussing treatment options in the management of early-stage hereditary breast cancer and should provide reassurance regarding the safety of administering RT to carriers of a germline BRCA1/2 mutation.
HALL ET AL1 FIRST identified the chromosomal region 17q21 as the locus for a gene linked to inherited susceptibility to breast cancer. The gene on 17q was isolated by Miki et al2 and designated BRCA1. A second breast cancer susceptibility gene was discovered on chromosome 13 and named BRCA2.3 These two genes are thought to account for approximately 5% to 10% of breast cancers, with most occurring in women younger than 50 years of age.4 The functions of BRCA1 and BRCA2 are at present unclear; however, recent data suggest that both may be involved in cellular response to DNA damage.4,5 A direct interaction between BRCA2 and the mouse homologue of Rad 51 has now been identified,5 suggesting that BRCA2 is a cofactor in the Rad-51–dependent repair of double-strand breaks. Studies by Sharan et al5 also demonstrated that embryonic mouse cells in which BRCA2 had been inactivated could not recover from gamma radiation damage. In addition, colocalization and coimmunoprecipitation studies have shown that BRCA1 protein interacts indirectly with Rad 51.6 This suggestion of a functional interaction between the two proteins supports the hypothesis that BRCA1 and BRCA2 are involved in the maintenance of genomic integrity. Although these data suggest a basic role of BRCA1 and BRCA2 in response to DNA damage, little is known about the radiation sensitivity of breast tissue in women who are carriers of a mutation in either gene. The potential for increased susceptibility of cells carrying a mutated breast cancer susceptibility gene to ionizing radiation would be critical in determining the appropriateness of radiation as a therapeutic tool in this group of women. Therefore, we asked the question of whether heterozygosity for either a BRCA1 or BRCA2 mutation would result in an increased sensitivity to ionizing radiation such that radiotherapy-associated complications and/or tumorigenic potential would be greater in patients with a germline mutation as compared with women having two wild-type copies of the gene. The goals of the present study were to identify, through high-risk clinics, women with either stage I or II breast cancer who, through genetic testing, were known to have a BRCA1/2 germline mutation and had been treated with radiotherapy to the intact breast, and to compare their rates of radiation-associated complications, local (breast) recurrence, distant failure, and overall survival with those from a matched cohort of women with sporadic breast cancer.
A multi-institutional collaboration was established in which investigators from nine institutions identified women with breast cancer treated in the United States and Canada with breast-conserving therapy and known to carry a germline BRCA1/2 mutation. Clinical data were abstracted through chart review using data entry forms at collaborating institutions. The data were entered in a centralized database at the University of Michigan where they were assigned a unique identifier to maximize confidentiality.
Study Design
Genetic Cohort Established methods used for mutation screening included protein-truncation test for mutations in exons 10 and 11 of BRCA1 and exon 11 of BRCA2, screening for founder mutations in the Ashkenazi Jewish (AJ) population (185delAG, 5382insC, 6174delT), conformation sensitive gel electrophoresis, allelic discrimination assay, and direct sequencing of DNA.7,8 The actual sequence variant in either gene was documented by direct DNA sequencing for aberrant bands observed. Seventy-one mutations were known to result in a truncated protein and were considered functional (deleterious) mutations; two additional patients had mutations of unknown significance. Although inclusion of these two mutations did not alter the statistical significance of the analyses, they were excluded such that only unequivocal disease-associated mutations were included in the genetic cohort.
Sporadic Cohort
Data Analysis Follow-up information was obtained by investigators on rates of in-breast recurrence, contralateral breast cancer, distant failure, and death. The period of follow-up was defined from the time of biopsy to the date of last patient contact for surviving patients. Due to the nature of the study, observation time was defined as the date of biopsy to time of analysis. The observation time was then used to verify that both cohorts had comparable time to experience the end points of interest. A local-only (breast) failure as first site of failure was defined as a breast-only failure. A local failure as a component of first failure included all breast failures, whether isolated or concurrent with regional or distant failure. A patient was considered relapse-free if continuously free of disease from the completion of radiotherapy to the last follow-up visit. Due to the matching of women in this study design, data collected could have been correlated within sets, affecting the estimation of variation and the resulting tests of significance. Comparisons between cohorts were adjusted for matching in several ways. The odds of having a genetic mutation was compared between groups defined by clinical and pathologic characteristics using conditional logistic regression (Proc PHreg, SAS Software Version 6.12; SAS Institute, Carey, NC). When group sizes were small, exact conditional logistic regression was used (LogXact Version 1.1; Cytel Software Corp, Cambridge, MA). Similarly, the odds of a severe adverse event were compared between cohorts using conditional logistic regression. When the amounts of missing data were small, sets of patients were excluded. Otherwise, M:N matching, when the number of cases and controls per set is allowed to vary, was used to maximize the information available for analysis.12 With M:N matching, the ratio of controls (M) to cases (N) within a particular matched set may be either 3:1, 2:1, or 1:1, depending on the number of the original three controls who were missing information with respect to the factor of interest. Comparisons between BRCA1 and BRCA2 were made using the Wilcoxon Rank Sum test or Fisher’s exact test. These groups were assumed to be independent. The time to local failure, disease-free survival and overall survival were estimated from the date of diagnosis for each cohort using Kaplan and Meier methods.13 However, because of the correlation of survival times between matched sets, a robust "sandwich" estimator of the variance14 was used to assess significance within a Cox proportional hazards regression model (S-plus Version 5; MathSoft Inc., Seattle, WA) Potentially, a selection bias exists for the comparison of these end points between cohorts. Specifically, woman with a genetic mutation needed to survive long enough after diagnosis to be tested and then included in this study. No similar criterion was placed on the women matched to this index woman. To attempt to minimize this bias, comparisons between cohorts are adjusted for those factors that were unbalanced between the cohorts that could therefore differentially affect recurrence and survival end points. These factors included race, medullary histology, estrogen and progesterone receptor status, and nuclear and histologic grade. Because of the frequency of missing data, rather than excluding cases, cases with unknown status were combined into the group referred to as "other."
Seventy-one cases of breast cancer in women with BRCA1/2 mutations treated with breast-conserving therapy for stage I or II disease were identified from the following institutions: 17 from the University of Toronto; 15 from the British Columbia Cancer Agency; nine from the University of Utah; eight from the University of Pennsylvania; six from the Joint Center for Radiation Therapy/Dana Farber Cancer Institute; five from the University of Chicago; five from Georgetown University; four from the University of Michigan; and two from Yale University.
Matching Summary Patients were diagnosed and treated between March 1980 and October 1997 in the genetic cohort and November 1980 and December 1997 in the sporadic cohort. As listed in Table 1, the genetic and sporadic cohorts were well matched by age at diagnosis and observation time. Of the 213 matches, 88% were from the same institution as the genetic case. The median follow-up time for the surviving patients was 5.3 years (range, 0.7 to 16.4 years) for the genetic cases and 4.6 years (range, 0.3 to 16.9 years) for the sporadic cases.
Clinical and Pathologic Characteristics As listed in Table 2, patients in the genetic cohort had tumors with a higher nuclear and histologic grade, negative estrogen and progesterone receptors, and medullary histology compared with the matched sporadic cases. The pathologic characteristics of the cancers in the genetic cohort were compared by germline mutation (Table 3). BRCA1-associated malignancies had a higher nuclear grade (P = .05) and a trend toward a higher histologic grade (P = .1) compared with BRCA2-associated cancers. Tumors associated with BRCA2 mutations were more likely to be estrogen and progesterone receptor–positive compared with tumors associated with BRCA1. For all subsequent analyses, the individual BRCA1 and BRCA2 groups were combined into a single genetic cohort.
Treatment Characteristics Surgical treatment by cohort. There were no significant differences between the genetic and sporadic cohorts with respect to the type of surgery and the final gross and microscopic margin status. Ninety-two percent of the sporadic cases underwent a lumpectomy/gross total excision compared with 96% of the genetic cases (P = .3). Ninety-nine percent of margins were grossly negative in the 203 sporadic cases for which the margin status was known, compared with 98% of the 64 cases with known margin status in the genetic cohort (P > .99). Margins were microscopically diffusely positive in 4%, focally positive in 8%, close (< 2 mm) in 6%, and negative in 82% of the sporadic cohort compared with 0%, 10%, 3%, and 86%, respectively, in the genetic cohort (P = .2). Radiotherapy treatment by cohort. The median fraction size to the breast was 2 Gy in both cohorts (range, 1.8 to 2.75 Gy). There were no significant differences in dose by radiotherapy field between the two cohorts. Specifically, the median doses delivered to the breast and breast plus boost were 46 Gy and 60 Gy, respectively, for both cohorts. The median doses to the supraclavicular nodes, axillary nodes, and internal mammary nodes for the genetic and sporadic cohorts were 45 Gy and 46 Gy (P = .3), 43 Gy and 46 Gy (P = .6), and 45 Gy and 47 Gy (P = 1.0), respectively. Similarly, there were no significant differences between the two cohorts in the radiotherapy fields treated, ie, breast only, breast plus supraclavicular nodes, breast plus supraclavicular plus axillary nodes, or breast plus supraclavicular plus axillary plus internal mammary nodes (P = .6; data not shown). One patient in the sporadic cohort was treated to the breast and internal mammary nodes only. Systemic treatment by cohort. Fifty-six percent of patients in the genetic cohort received chemotherapy compared with 50% in the sporadic cohort (P = .3). Twenty-four percent of the patients in the genetic cohort received a doxorubicin-based chemotherapeutic regimen compared with 23% in the sporadic cohort; 30% and 27%, respectively, received methotrexate-based chemotherapy. Twenty-four percent of patients in the genetic cohort received tamoxifen compared with 29% in the sporadic cohort (P = .4).
Radiation-Associated Complications
The incidence of chronic radiotherapy adverse events by cohort is listed in Table 5. Using the RTOG/EORTC scoring criteria, there were no significant differences in the rates of chronic skin, subcutaneous tissue, lung, or bone complications between the genetic and sporadic cohorts. Ninety-seven percent of the women in the genetic cohort had either grade 0 or 1 skin toxicity compared with 96% in the sporadic cohort (P = .7). Ninety percent and 87% of patients in the genetic and sporadic cohorts, respectively, had minimal to no skin fibrosis (P = .5); 99% of patients in the genetic cohort had no recorded lung or bone complications compared with 100% and 99%, respectively, in the sporadic cohort.
Patterns of Recurrence: Rates of In-Breast Recurrence There were no significant differences in rates of recurrence in the treated breast between the genetic and sporadic cohorts at 5 years. There were three local (breast) recurrences in the genetic cohort and eight in the sporadic cohort. Each of the recurrences in the genetic cohort and seven of eight recurrences in the sporadic cohort represented an isolated local recurrence; one of the eight patients in the sporadic group experienced a simultaneous breast and distant failure. For all isolated breast recurrences in each cohort, salvage treatment with mastectomy was successful. The 5-year estimates for local control after a local failure as component of first failure were 98% and 96% for the genetic and sporadic cohorts, respectively (hazard ratio, 0.85; P = .8; Fig 1). No patients in the genetic cohort developed metastatic disease after breast recurrence at the time of last follow-up; two (29%) of seven patients who experienced an isolated local failure in the sporadic cohort subsequently developed metastatic disease.
The median time to local failure was undefined using actuarial methods. Of the three patients in the genetic cohort who experienced local failure, the median time to local recurrence was 8.2 years. This was compared with 3.1 years for the sporadic cohort. Two (67%) of the three in-breast recurrences in the genetic cohort occurred elsewhere in the breast, compared with five (63%) of eight breast recurrences in the sporadic cohort.
Survival and Other Cancers
Our results demonstrate no significant differences in acute and chronic toxicity in women with a BRCA1/2 mutation compared with matched sporadic controls, and comparable rates of local control and relapse-free and overall survival between the cohorts at 5 years. Thus despite the theoretical concern that ionizing radiation, which is known to cause double-strand DNA breaks, could have a deleterious effect on breast tissue heterozygous for genes associated with DNA repair, our data showed no evidence of an adverse effect. They also suggest the DNA damage response of cells with only one normal copy of either BRCA1 or BRCA2 is functionally not impaired. Genetic and sporadic cases were matched within institution, when possible, to control for differences in surgery, radiotherapy, and systemic therapy and to minimize therapy-associated factors that could affect toxicity. After controlling for treatment-related factors, complication rates were similar between the genetic and sporadic cohorts. Gaffney et al15 also found similar rates of radiation-associated side effects in their series of BRCA1/2 patients treated with radiotherapy compared with historical controls. Therefore, it seems that heterozygosity for either a BRCA1 or BRCA2 mutation does not confer increased sensitivity to radiation and that clinical indications to deliver radiotherapy should not be altered on the basis of the presence of a germline BRCA1/2 mutation. A potential limitation of the present study is the possible underreporting of toxicity data, especially acute toxicity, due to retrospective data acquisition. Data, however, were acquired for both groups in a similar manner, and the rates reported in this series are comparable to those of other published breast conservation series.16-18 Therefore, it is unlikely that the retrospective retrieval of the toxicity data significantly affected the accuracy of the results. The pathologic findings in the BRCA1/2 carriers in the present series are consistent with those of published reports by others.19-22 We found a higher percentage of BRCA1-associated lesions to be of medullary histology and high nuclear and histologic grade. The Breast Cancer Linkage Consortium reported a significantly greater number of mitoses and degree of pleomorphism in the BRCA1-associated malignancies compared with BRCA2-associated lesions and controls.21 Our series also found a greater number of estrogen and progesterone receptor–negative lesions in the BRCA1-associated malignancies compared with lesions from BRCA2 carriers, which is also in agreement with published results.20,22,23 Among breast cancers arising in women screened of AJ descent, Karp et al20 found only 19% of tumors with BRCA1 mutations to be estrogen receptor–positive compared with 73% in tumors without a mutation. These results compare with 100% (four of four) estrogen receptor–positive BRCA2 breast cancers. Therefore, it seems that BRCA1-associated breast cancers may be biologically distinct from tumors associated with BRCA2, and recognition of these differences may have implications for treatment and possibly chemoprevention. Limited information has previously been available regarding outcome after the use of breast-conserving therapy in women with hereditary breast cancer. Initial reports in patients at risk for a familial breast cancer gene mutation yielded somewhat conflicting results, because family history only was used as a surrogate for genetic testing.24-29 Potential limitations of these studies included the tendency to overestimate the likelihood of a mutation based on early data of higher attributable risk, the difficulty in obtaining an accurate positive (and negative) family history, and the lack of a uniform definition for high risk. Smaller studies have recently provided some information in women with a germline BRCA1/2 mutation. Verhoog et al22 reported a 14% rate of recurrence at 5 years in 18 BRCA1/2 carriers at 5 years compared with 16% in sporadic controls. All tumor stages were included in this series, although approximately 80% of the patients were noted to have stage I or II disease. In a series from Memorial Sloan-Kettering Cancer Center, 15% of patients with a mutation developed an ipsilateral breast recurrence at 5 years compared with 4.5% in controls.30 These results suggest a higher in-breast rate of recurrence than the 1% to 2% rate per year that is commonly reported in most North American breast-conserving therapy series for stage I or II disease31 and may reflect factors such as limited patient accrual or differences in treatment-related factors by cohort. Alternatively, these results could reflect the biologic differences of breast cancer associated with a germline BRCA1/2 mutation. A recent study from Yale evaluated patients treated with breast-conserving therapy who developed an in-breast recurrence and compared the rates of BRCA1/2 mutations in this group with a control group of patients not experiencing a recurrence.32 The authors found that 15% of the patients who had an in-breast recurrence had a BRCA1/2 mutation compared with a 7% incidence of BRCA1/2 mutations in patients without a breast recurrence, and concluded, on the basis of a sample size of eight cases, that early-stage breast cancer patients experiencing in-breast tumor recurrence have a disproportionately high frequency of BRCA1/2 mutations. The concerns and potential pitfalls of using this experimental design to study a possible cause and effect between radiotherapy in carriers of a germline mutation and rates of in-breast tumor recurrence were discussed in an accompanying editorial.33 This study did, however, suggest a higher rate of second primary breast cancers in BRCA1/2 carriers compared with noncarriers, consistent with data presented here. To our knowledge, our study represents the largest series ever published of breast-conserving therapy in known BRCA1/2 mutation carriers, and the results demonstrate a 2% rate of local failure as a component of first failure in the genetic cohort compared with a 4% failure rate in matched controls at 5 years. Follow-up, however, is limited. Although the actuarial estimate of the median time to failure is currently undefined, the median time to failure for the three tumor recurrences observed to date among the genetic cohort was 8.2 years versus 3.1 years among the eight observed failures in the sporadic cohort. Because of small numbers and short follow-up time, it would be premature to conclude that among women who experience local failure, those with genetic mutations had a longer time to failure. It will, therefore, be critical to extend follow-up for all patients in this series to assess potential differences between the cohorts in the rates of tumor recurrence in the breast with time. As expected, the risk of contralateral primary breast cancer was significantly greater in the genetic cohort than in the sporadic cohort, with a 20% actuarial risk of developing a new lesion at 5 years in women with hereditary breast cancer who had not undergone prophylactic mastectomy compared with 2% in the sporadic cohort (P < .0001). Although this risk was significantly greater in women with a germline BRCA1/2 mutation compared with the sporadic cohort, it seems conservative when compared with an estimate of 40% by the age of 45 years from an earlier publication by Ford et al and the Breast Cancer Linkage Consortium.34 As discussed by others, data from the linkage studies may represent an overestimate of the risk compared with that seen in families more commonly evaluated in high-risk clinics.10,35 Explanations of the observed increased risk of a contralateral breast cancer in carriers of either a BRCA1 or BRCA2 mutation have focused primarily on the pathogenesis of the disease in the presence of these genetic alterations. A less plausible argument, proposed by some, suggests that scatter from therapeutic irradiation could contribute to the increased rate of second primary breast cancers. Although most studies in the literature do not support this hypothesis,36-39 one large case-control study by Boice et al40 did demonstrate an increase in the risk in contralateral breast cancers in women who were younger than 45 years when treated with radiotherapy for breast cancer. The majority of these patients were treated before 1960 with techniques and equipment not used in contemporary radiotherapy practices. Randomized trials comparing breast-conserving surgery and radiation with mastectomy that have published rates of contralateral events have not demonstrated any differences between the groups in the risk of developing a second primary breast cancer41-44; however, the percentage of women carrying a breast cancer susceptibility gene in these studies is unknown. In women known to carry a BRCA1 mutation, Verhoog et al22 reported a rate of contralateral breast cancers of 19% at 5 years in a series in which two thirds of the women were treated with mastectomy. Given the similar rate of contralateral breast cancers seen in the current radiotherapy series, our data do not suggest an increased rate of second cancers in the opposite breast after scatter radiation from ipsilateral breast treatment at 5 years; further follow-up is warranted. It is always prudent, however, to avoid radiation to uninvolved tissues when possible. Radiation treatment planning techniques such as omission of a medial wedge and the use of intensity-modulated tangential-beam irradiation have been shown to limit contralateral breast dose45,46 and should be encouraged in the management of these patients. A striking finding in the present series was the comparison of the rates of contralateral breast cancers and ipsilateral recurrences/new primaries in the genetic cohort. Despite a 20% rate of contralateral new breast cancers in the women with a BRCA1/2 mutation, only 2% developed a recurrence/new primary in the irradiated breast at 5 years. This significant reduction of breast cancer in the irradiated breast compared with the contralateral untreated breast suggests the presence of multicentric disease throughout the mammary tissue, ie, a field cancerization effect, in women who are carriers of a germline BRCA1/2 mutation and the ability of radiotherapy to sterilize subclinical disease. Continued follow-up of events in both the involved breast and the contralateral breast will be essential in determining whether radiotherapy delays or prevents the development of new breast cancers over time. How should our results factor into the management decisions of women who are known carriers of a deleterious BRCA1/2 mutation? With the risk reduction in the development of breast cancer in high-risk women demonstrated by Hartmann et al47 with prophylactic mastectomy, surgical prophylaxis seems to be a reasonable strategy to consider. However, the recent overview of tamoxifen trials has shown a 47% proportional reduction in contralateral breast cancers after 5 years of treatment with tamoxifen,48 and the National Surgical Adjuvant Breast and Bowel Project P-1 study has similarly demonstrated a 49% reduction of invasive breast cancers using tamoxifen chemoprevention.49 Although the degree of benefit from tamoxifen in these studies in BRCA1/2 carriers has not yet been defined, using family history as a surrogate end point suggests an approximate 50% reduction of invasive breast cancer in patients with one or more first-degree relatives with breast cancer.49 Recent data have also demonstrated an approximate 50% reduction in breast cancer risk in BRCA1 mutation carriers after bilateral prophylactic oophorectomy.50 Thus in the absence of randomized studies comparing survival after prophylactic mastectomy with surveillance with chemoprevention, many patients may elect surveillance. Should patients later develop an early-stage breast cancer and wish to consider breast conservation, our data suggest rates of control in the affected breast equal to those achieved in sporadic breast cancer at 5 years. It is clear, however, that with the increased rate of contralateral breast cancers with time, management decisions for a known breast cancer should be based not only on the involved breast but also on the opposite breast. Detailed discussions of either bilateral mastectomies (ie, therapeutic and prophylactic) or breast-conserving therapy with chemoprevention and careful surveillance should be held with patients who are known to carry a breast cancer susceptibility gene, and decisions should be individualized on the basis of patient preference. In summary, the present report demonstrates comparable rates of tumor control, survival, and radiation-associated complications at 5 years between carriers of a BRCA1/2 mutation and women treated for sporadic disease. Although additional follow-up is needed, these data should aid patients and their health care providers in discussing the relative merits of breast-conserving treatment in the management of early-stage hereditary breast cancer and should provide reassurance regarding the appropriateness and safety of clinically indicated adjuvant radiation treatment.
We thank Tim Rebbeck, David Schottenfeld, Carolyn White, Kathy Calzone, Kelly Metcalfe, Caroline Trevisan, Shelly Cummings, and Ethan Cash for their assistance.
Presented in part at the Thirty-Fifth Annual Meeting of the American Society of Clinical Oncology, May 15-18, 1999, Atlanta, GA.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
