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AN UPDATE ON RADIATION THERAPY IN BREAST CANCER
ADVANCES IN BREAST CANCER THERAPY
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AN UPDATE ON RADIATION THERAPY IN BREAST CANCER Silvia Formenti, MD, and Garth Green, MD
Radiation therapy plays an important role in the management of both invasive and noninvasive breast cancer. During the last 20 years, the availability of radiation therapy has made it possible to test the feasibility and safety of breast preservation after the diagnosis of earlystage breast cancer. Two recent meta-analysesZ1,63 of prospective randomized trials comparing mastectomy to breast preservation and radiation have demonstrated the equivalence of the two modalities in terms of local control and overall survival. Further, one of the meta-analyses has detected that patients with node-positive disease who underwent breast preservation had a survival advantage compared with the mastectomy arm.63Despite this evidence, in the United States less than half the patients eligible for breast preservation surgery receive such treatment. At least in some cases, the fact that radiation therapy is required after partial mastectomy affects the decision about mastectomy versus breast preservation. Many patients maintain a deep-rooted fear of radiation. In some places radiation therapy facilities are not easily accessible. Because the conventional postoperative course of radiation requires daily attendance (Monday to Friday) for 5 to 6 weeks, it is often perceived as a major inconvenience. Most recently, attempts were made to question critically whether, at least in some subsets of patients with carcinoma in situ or with early-stage breast cancer, radiation could be modified or omitted after segmental mastectomy. At the same time, recent data from
From the Kenneth Norris Jr Cancer Center, University of Southern Califomia, Los Angeles, California HEMATOLOGY/ ONCOLOGY CLINICS OF NORTH AMERICA
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two randomized trials have re-opened the option of adding radiotherapy after mastectomy, at least in patients with node-positive disease. Finally, the conventional locoregional approach to locally advanced breast cancer is also under scrutiny, and studies are ongoing to test safety and feasibility of breast preservation with radiation instead of modified radical mastectomy. This article summarizes some of the ongoing controversies concerning the use of radiation therapy in the multidisciplinary management of breast cancer.
THE ROLE OF RADIATION THERAPY IN THE BREAST CONSERVATION APPROACH TO CARCINOMA IN SlTU The rate of breast cancer detection has accelerated because of the ability of mammography to identify small, nonpalpable breast lesions. The utilization of mammography may be capable of diminishing mortality by as much as 40% in the postmenopausal population, for whom mammographic imaging is most accurate. Mass mammography screening has resulted in large numbers of suspicious nonpalpable lesions being biopsied. Although most lesions biopsied are benign, approximately 10% to 30% of those excised at any institution are found to be malignant.13,l9 Now, approximately 13%of newly diagnosed breast cancers are ductal carcinoma in situ (DCIS),69compared with 2% in 1980, when most DCIS were diagnosed either as a palpable mass, because of bloody nipple discharge, or as an incidental finding in a biopsy performed for other reasons.7* By definition, DCIS represents a proliferation of malignant cells confined to the ductal system without evidence of invasion into the basement membrane on light microscopy. Strictly speaking, there is no risk of regional or distant dissemination. The ultimate risk of mortality from this lesion, then, is related to the concomitant presence or development of an invasive breast cancer with its attendant risk of distant metastases. Preventing this development is the major issue in the management of DCIS. Multiple options are available for women with DCIS, including a wide excision, wide excision with radiation, or mastectomy. In evaluating these different approaches, one must assess the risk of an ipsilateral invasive or noninvasive breast recurrence, the effect and prognosis of such a recurrence, and, ultimately, the risk of death secondary to breast cancer. Although mastectomy offers high rates of local regional control (96%-100%) and cause-specific survival (96%-100%), it seems radical, especially when early-stage invasive cancers can be treated with breast
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c~nservation.~~, 92 Therefore, breast-preserving approaches that include wide excision with or without radiation have been investigated. Currently, the biggest controversy centers around which patients may be successfully treated with excision alone. In most series of wide excision alone, patients are highly selected for small, nonpalpable masses diagnosed by microcalcifications at mammography, making direct comparisons to radiated patients sometimes difficult. For instance, in Lagios and colleagues’ seminal series of patients treated with wide excision only, eligible patients had DCIS which was a mammographically detected area of microcalcifications measuring 25 mm or less with negative resection margins and negative postbiopsy rnamm~grarn.~~ In a recent update, Lagios reported a 17% rate of breast cancer recurrence with a median follow-up of approximately 10 years.52Other investigators have presented similar results.u, In general, recurrence rates are correlated with the method of detection of the original DCIS and its histologic features: a palpable mass, high nuclear grade, comedo histology, and presence of necrosis are poor prognostic featuresm6 Approximately half these recurrences will be invasive, and almost all will be in the same region as the initial lesion. Salvage rates are good for both noninvasive and invasive recurrences, being close to 100% and approximately 75%, respectively. In an alternative approach analogous to that applied in early-stage invasive disease, radiation has been delivered after wide excision for DCIS. Selection factors are less strict than those applied by Lagios et al, making more patients potentially eligible for breast preservation. Crude rates of breast cancer recurrence range from 0% to l8%, with causespecific survivals of 96% to 59, 86, 88 Solin and colleagues reported the results of 268 women treated with excision and irradiation at 10 institutions in the United States and Europe. At a median follow-up of 10.3 years, there were 45 ipsilateral breast cancer recurrences. The 15year actuarial breast cancer recurrence rate was 19%, and the 15-year actuarial cause-specific survival was 96%. Median time to failure was 5.2 years.86 Failure to remove residual calcifications on postbiopsy mammogram has resulted in a high risk of breast cancer recurrence in the small numbers of patients reported.59,85 The effects of other clinical factors, including bloody nipple discharge, age, and family history, are inconclusive from available data. The influence of pathologic features on breast cancer recurrence has also been The collaborative group identified an increased risk of failure for high nuclear grade, comedo carcinoma at 8 years.86,87 With further follow-up, however, these factors were no longer significant, reflecting only a difference in the median interval to breast cancer recurrence, the intervals being 3.1 years for high nuclear grade, comedo carcinoma and 6.5 years for the low grade or
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noncomedo DCIS.86Silverstein and associates reported similar findings, suggesting that series with short follow-up will overestimate the effect of high grade or comedo histology on recurrence rates.83Recent reports also suggest that wide excision with negative microscopic margins is extremely important in reducing the risk of breast cancer recurrence.29, 85, Silverstein and associates have proposed a treatment algorithm that uses tumor size, margin width, and nuclear grade/necrosis to predict breast cancer recurrence ~ates.8~ In Silverstein's retrospective series, irradiated patients who had negative margins, low / intermediate grade tumors, and no necrosis had similar risk of an invasive recurrence, similar patterns of breast cancer recurrence, and similar rates of salvage to those of patients treated with excision alone. Although this classification may help select appropriate patients for breast conservation, its validity must be confirmed by other data sets and, ideally, tested by a prospective randomized trial. At the present time, the available alternatives remain mastectomy or segmental mastectomy followed by whole-breast radiation.
CONTROVERSIES IN THE MANAGEMENT OF POSTMENOPAUSAL WOMEN WITH T1 CANCERS
Another effect of the implementation of mammographic screening is the emergence of a new patient population: postmenopausal women with nonpalpable tumors, detected at routine mammography and frequently measuring less than 2 cm (i.e., T1 tumors at TNM staging). The natural history of these tumors is not well known because data are scarce, and there is no general agreement on the method used for measuring the volume. Because of this lack of information, controversy exists regarding the correct management of these patients. For instance, the need for axillary node dissection has been questioned because, among invasive cancers of this size, lymph-node involvement is rarely observed: the incidence in pTla (0.5 cm or less in greatest dimension) is O%, pTlb (more than 0.5 cm but less than 1 cm in greatest dimension) is 7%, pTlc (more than 1 cm and less than 2 cm) is 13%.2,13,96 Moreover, nodal status is an imperfect predictor of the risk for systemic relapse.2o,46. 63, 96 In most cases the main role of axillary dissection is to guide the choice of adjuvant systemic therapy. Consequently, the role of axillary node dissection is controversial for postmenopausal women with T1 cancers who will, in any case, be treated with adjuvant tamoxifen, as supported by the significant benefit recognized by the meta-analysis of adjuvant treatments? These considerations have significance because of the reported potential long-term morbidities of axillary node dissection, including lymphedema, chronic shoulder
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pain, and hypoesthesia. During the last few years many breast cancer centers have adopted the policy of sparing axillary node dissection to postmenopausal women with Tla and Tlb primary tumors. Some investigators have advocated radiation to the axilla as a substitute for surgical dissection.37,lo2 For instance, with a median follow-up of 54 months, Wazer et a1 found no regional nodal recurrences among 94 postmenopausal breast cancer patients who had undergone breast and regional node radiation.lo2Moreover, four studies of selected postmenopausal women with cancers measuring less than 1 cm who were spared axillary dissection or radiation have reported axillary recurrence rates of 0% to 7%.22,38, 45, lo3The authors believe that treatment guidelines should be determined and implemented nationally. At this time, the management of the axilla needs to be discussed with each patient, and a careful description of the risk/ benefit ratio must be provided. Another area of controversy relates to the issue of whether wholebreast radiation therapy is necessary for this patient subset.'" 56, 79, 91, 99 Originally, the Cleveland Clinic reported an incidence of local recurrence of 10.9% among a series of women who had undergone breast-preserving surgery only.16 This rate is quite different than that found in a prospective randomized trial by the National Surgical Adjuvant Breast and Bowel Project (NSABP-06) at 12 years in which there was a local recurrence rate of 35% in the women receiving segmental mastectomy alone, compared with 10% in the women who also received r a d i a t i ~ n . ~ ~ The NSABP-06 incidence is consistent with the findings from pathology series. Holland et a1 elegantly documented the incidence of multifocality/ multicentricity among small breast cancers. For lesions measuring 2 cm in diameter or smaller, other microscopic foci (including lymphatic emboli) of invasive cancer outside a 2 cm margin from the primary tumor were detected in 14% of the specimens.a These rates are similar to those reported by other authors30,51 and by Rosen et al, who analyzed 203 mastectomy specimens and identified multicentricity in 26% of the breasts with index lesions measuring less than 2 cm and in 36% among those with index lesions measuring more than 2 and less than 4 cm.77 Results from five prospective randomized trials are available to clarify this issue (Table 1). Although these studies differ in their criteria for patient eligibility, type of surgery, and duration of follow-up, they are consistent in confirming superior local control when radiation is added to surgery. More can be learned by carefully analyzing each study. The study conducted at the Netherlands Cancer Institute randomized 381 T1 breast cancer patients (including both premenopausal and postmenopausal women) to sector resection with or without radiation. Predictably, at 5-year follow-up, a significantly higher rate of local recurrence occurred in the arm receiving segmental mastectomy alone (18.4%)
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Table 1. PROSPECTIVE RANDOMIZEDTRIALS OF BREAST-PRESERVING SURGERY WITH OR WITHOUT ADJUVANT RADIATION THERAPY ~
Author (Re9
Fisher (27) Clark (14) Forrest (34) Veronesi (99) Liligren (56)
Number Cancer of Size Patients (cm)
1362 837 585 567 381
4
4 4 4
2
+
Type of Surgery
Local Resection Surgery Alone
wide excision wideexcision wide excision quadrantectomy sectorresection
35 35 25
9 18
Surgery Radiation Therapy
10 11 6 C1
2
Follow-up (years)
12 7.5 6 3.5 6
compared with the arm receiving segmental mastectomy and postoperative radiotherapy (2.3%).Noticeably 77% of the recurrences in the surgery-alone arm occurred within the initial tumor bed. The findings suggest that adjuvant radiation to a volume inclusive of the tumor with sufficient margins might be adequate to affect significantly the risk of local recurrence among women with a particularly low risk. For instance, in this study all patients carried tumors measuring less than 2 cm that were removed with generous margins (sector resection). It would be particularly interesting to investigate a reduction of the target volume of radiation, both to decrease exposure of normal tissue and to explore This area of research should more convenient fractionation study women who are predicted to carry the lowest risk of recurrence: women with completely excised T1 tumors who are older than 55. The study from Veronesi and co-workers seems to corroborate the finding of the Netherlands Cancer Institute. Veronesi et a1 employed a more extensive surgical procedure that allows larger excisional margins (quadrantectomy)and found no additive benefit by adding radiotherapy postquadrantectomy in women older than 55.% Since in the United States breast-preservation surgery is mostly tylectomy a form of segmental mastectomy that achieves less generous margins than quadrantectomy and results in better cosmetic outcome, adjuvant radiotherapy to the tumor bed could compensate for less extensive surgery. Several investigators have explored the use of brachytherapy directed to the tumor bed, without external irradiation to the rest of breast tissue. These pilot studies have demonstrated feasibility, but long-term data on local control are not available yet.25,26* 33,97, looThe Radiation Therapy Oncology Group (RTOG) is conducting a multi-institutional study of brachytherapy alone after segmental mastectomy. Although the technique has been shown to be quite effective in breast cancer and requires only 5 to 7 days of treatment, it is invasive and, if low dose rate brachytherapy is prescribed, it demands the patient's isolation during radioactive treatment. Moreover, long-term cosmetic results are not yet available, and the risk of
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fibrosis and induration at the implant site remains a concern, especially since it impairs routine physical examination of the breast.33,97
UPDATE OF POSTMASTECTOMY RADIATION THERAPY
The recent reports from two prospective randomized trials of mastectomy with and without radiation have re-opened the discussion of the effect of local control on the ultimate survival from breast cancer.67, 74 Previous studies had provided evidence that optimization of local control produces small improvements in overall survival, at least among some patient subsets.', 5, 58, 98 The two more recent studies from Danish and Canadian investigators have become the central subject of tumor boards and interdisciplinary conferences all over the country. The pertinent discussion can be structured by asking several consecutive questions. First, are the findings of the Canadian and Danish studies translatable to the ongoing practice of breast oncology in United States? Most breast cancer centers in the United States will challenge the adequacy of the axillary dissection received by the patients in these two series. Because most of the women in the series had undergone less extensive axillary staging, it is possible that at least to a certain extent some stage-shift phenomenon could account for a regional recurrence rate of approximately 30% detected in these two studies, compared with the standard rates in the United States of 6% to 13%. In other words, reduced surgical staging could underestimate the actual nodal involvement so that patients are understaged. This possibility is reinforced because, when compared with published series of studies in the United States, more nodal recurrences were detected in each nodal subset (both for patients with one to three and for those with four or more involved nodes).&12. 36, 48. 98 At present the issue remains open, as it is quite possible that the addition of nodal radiation could have compensated for potentially suboptimal surgical management of the axilla. To complicate the question, the radiation techniques employed in both studies are now seldom used in the United States, where internal mammary nodes are not electively included in most post-mastectomy radiation protocols. This difference makes comparison of the Danish and Canadian series with United States radiation series impossible. For instance, in a recently reported retrospective analysis of the experience at the M. D. Anderson Cancer Center, the risk of local recurrence was reduced from 11%in patients receiving 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) alone to 5.6% in patients receiving FAC plus radiation therapy. No difference in survival was found, probably because most patients
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were selected to receive radiation based on their estimated increased risk for local r e c ~ r r e n c e . ~ ~ Finally will the survival advantage detected remain at 20-years follow-up? A previous meta-analysis of radiation trials detected a breast cancer cause-specific survival advantage of 3% at 10 years accompanied by a 2% increased hazard of mortality from other causes, resulting in a nonsignificant overall benefit.17 It is possible that the findings of the Danish and Canadian studies represent the early results achieved by adding radiotherapy in a subset of women at increased risk; whether the use of modern radiation techniques in these trials would prevent long-term increased cardiac mortality among these women remains 70
How, then, to make best use of the information provided by the Canadian and Danish studies? Who are the patients who should undergo adjuvant radiation therapy and should the same radiation techniques be adopted? As eloquently pointed out by Recht et a1 in a recent editorial in the Journal of CZinicuZ OncoZogy, it is likely that, as is also reported for systemic therapy radiation therapy generates relatively consistent proportional risk reductions among different patients The question becomes at what point absolute risk should be considered sufficient to justify the potential morbidity and cost of adjuvant radiation. Although studies conducted among patients undergoing breast preservation treatment suggest that even a small reduction in risk of local recurrence is sufficient to justify radiation treatment for most women,39, a recent report demonstrated an increased risk of cardiovascular disease in patients with cancer in the left breast who had received adjuvant ~ a d i a t i o n ,so ~ ~that all efforts to shield the heart from the radiation ports are warranted. At this time these issues and their precise implications must be explained and discussed with patients. The American Society of Clinical Oncology (ASCO) has appointed an expert panel to review the existing published information and to design guidelines for postmastectomy radiotherapy that will be available to the public in 1999. CHEMORADIATION IN LOCALLY ADVANCED BREASTCANCER
Originally pioneered by DeLena and co-workers in Europe and by the M. D. Anderson Cancer Center in this country, the paradigm of primary or neoadjuvant chemotherapy followed by surgery, followed by prophylactic radiotherapy, has been extensively tested in locally advanced breast cancer (LABC).I0,Is, a 41, * 57, 93 These studies have proven the feasibility of sequential multimodality therapy. Local control rates in
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the range of 54% to 85% are obtained and are superior to those achieved in historical controls by radiation or surgery alone or by the combination of the two. Five-year survival rates of approximately 55% are achieved for the entire group of LABC patients, but, at subset analysis, stage IIIA consistently fares better than stage IIIB, with 5-year survival rates of 84% and 44%, respectively.44 What is the ideal local management after primary chemotherapy? It appears that in LABC no significant survival advantage is associated with the addition of mastectomy compared with a noninvasive local management by radiation therapy. The original study by DeLena et a1 of 132 women with LABC consisted of three cycles of vincristine and doxorubicin followed by randomization to radiation or surgery. No differences in disease-free survival or overall survival were found between the two arms.lSThe same results were obtained in a more recent study from the Cancer and Leukemia Group B (CALGB) which randomized 87 stage I11 patients after chemotherapy to either surgery or radiation. Although a higher local recurrence rate was identified in the radiation arm (27% versus 190/,),the rate of distant metastases was identical for both arms (25%) and, with a median follow-up of 37 months, there was no difference in survival between the two groups.71Finally, Buzdar et a1 found no difference in the rate of local recurrence when surgery was added to radiotherapy; however, the combination of the two modalities allowed a reduction in the radiation dose, resulting in less radiationinduced morbidity.l0 Encouraged by these data, several more recent clinical trials of LABC have been designed with the endpoints of both breast preservation and survival. With careful patient selection (based on the clinical and radiological response to primary therapy), 5-year local control is approximately 85% to 90%. When the entire series of LABC is analyzed (including patients deemed noneligible for breast preservation), 5-year breast-preservation rates of approximately 52% to 77% are achieved.l5> 60, 73, 95 Unfortunately, clinical evaluation of residual tumor does not reliably predict for pathological response: approximately one third of LABC patients found to have pathological clearance of tumor cells after primary treatment have residual palpable masses at physical examination, and a similar proportion of patients with clinical complete response have persistent disease in the pathology specimen.lO, 15,44, 60, 73, 95 Numerous noninvasive techniques to assess clinical response more accurately after primary chemotherapy are under investigation. Concurrent Chemoradiation: The University of Southern California Experience Since 1993 the University of Southern California (USC) interdisciplinary breast cancer group has followed a paradigm of clinical research
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that tests preoperative concurrent chemoradiation in LABC. The extent of the pathological response of the primary tumor is used as an endpoint to measure tumor resistance to the tested combination. The rationale behind this model is many-fold. First, the encouraging results achieved by concurrent chemoradiation in other tumor models have motivated the testing of this approach in LABC.S n,76 Second, this subset of women is generally at high risk for tumor persistence/local recurrence after chemotherapy and surgery, and their management must always include radiation therapy. Moreover, because it is easily biopsied, LABC is an excellent model for translational research. Tumor specimens obtained before treatment can be analyzed for potential markers that predict for response to the tested regimens, and biological profiles of the primary tumor are prospectively acquired for each patient studied. Associations of the markers tested with the extent of pathological response of the primary tumor can be explored to generate hypotheses to explain mechanisms of tumor resistance to the tested regimen. The first study of concomitant chemoradiation conducted at USC consisted of continuous infusion (c.i.) fluorouracil (5-FU) and concomitant radi~therapy.~~ The combination showed a synergistic effect in converting to resectability with primary wound closure all 35 originally inoperable patients. Clinical response (complete response [CR] plus partial response [PR]) measured by the interdisciplinary team 1 to 2 weeks before mastectomy was 72%. Pathological complete response (pCR) was defined as the clearance of invasive cancer in the breast and axillary contents. Pathological partial response (pPR) consisted of persistence of fewer than 10 microscopic foci of invasive tumor cells in the breast or in the axillary contents; a lack of pathological response (pNR) included any larger number of residual cancer cells in the breast or in the axillary contents. Persistence of DCIS was accepted and did not modify this classification for invasive disease. Pathological complete clearance of invasive tumors occurred in 7 of 35 patients (20%),and 5 other patients had only microscopic residual cancer (pCR + pPR = 34%), a remarkably high rate among this population of locally advanced, inoperable breast cancer As others have also reported no correlation was found between clinical response and pathological re~ponse,'~, n, 95 supporting caution in adopting breast-preservation protocols in this subset of women. Probably the most important result of this study is the preliminary evidence of the association of p53 status with pathological response. As part of the study design, all patients underwent pretreatment core biopsies of the primary tumor and a second core biopsy after 2 weeks of c.i. FU alone before combining radiation. The specimens were evaluated at immunohistochemistry for expression of the p53 protein product, HER2/neu and thymidylate synthase. Eleven of 21 patients (52%) with no evidence of p53 overexpression at immunohistochemistry (anindirect
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evidence for lack of mutation of the p53 gene) achieved a pathological response to the regimen, compared with 1 of 14 patients (7%) with overexpressed p53 ( P = 0.010).31At multivariate analysis, lack of p53 overexpression was the only independent prognostic factor for pathological response. This pilot study provided preliminary evidence for potential patient selection to a specific treatment for LABC. However, since most patients who overexpressed p53 failed to achieve a pathological response, it became important to investigate the use of drugs that may be differently affected by p53 status. Taxanes are indeed such lol, lo4 From the initial experience of concomitant FU and radiation, a study was designed of twice-weekly paclitaxel and radiation for patients with LABC. To expedite data accrual, three academic institutions, USC, New York University (NYU), and the Mayo Clinic, Jacksonville, have joined to conduct this study. Several rationales support the testing of taxanes and specifically studying paclitaxel. Paclitaxel is a very active drug in breast cancer, producing objective response in approximately 50% to 60% of patients with advanced breast cancer when used as initial therapy, and in about 20% to 25% of patients with advanced disease resistant to other chemotherapy agents.7,9,43, 66 Budzar et a1 have reported the results of a pilot study comparing paclitaxel with cyclophosphasmide, Adriamycin, and fluorouracil (CAF) in a primary chemotherapy setting for women with operable breast cancer. Similar pathological response rates were detected in the two arms, suggesting that single-agent paclitaxel is probably equivalent to CAF in inducing pathological r e s p ~ n s eMoreover, .~ paclitaxel is a promising drug for use in combination with radiation therapy. Experience acquired in different tumor sites suggests a synergistic effect of paclitaxel with concomitant 62 possibly resulting from paclitaxel-induced accumulation of cells during the G2/M phases of the cell cycle, which are indeed the most radiosensitive phases of the cycle.61,62 An ancillary study to the clinical protocol has been designed to measure in breast cancer the kinetics of mitotic and apoptotic changes induced by paclitaxel. The preliminary data support the use of a twiceweekly schedule to exploit most effectively the paclitaxel-induced G2 / M cell accumulation during the course of radiation therapy?*
CONCLUSIONS
During the past 20 years, the applications of the findings of molecular biology to the clinical setting has revolutionized the practice of medicine. While efforts to improve the efficacy of the available treatment modalities are ongoing, another approach to increase efficacy of treatment is by better matching patients with the available treatment tools.
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In oncology, more and more attempts are being made to preselect patients for treatment by identifying tumor markers that predict for response. In breast cancer, for instance, the presence of HER2 / neu overexpression has selected a subset of tumors exquisitely sensitive to doxorubicin-based adjuvant ~hemotherapy.6~ Although indications for radiation therapy remain at this point quite general, research should focus on the identification of specific biological markers that predict for high risk of local recurrence.lo5 In addition, studies of the effects of radiation therapy on the stromal and vascular components of tumors are likely to reveal new applications for this treatment modality. Meanwhile, results from randomized trials and the use of TNM staging remain the main available tools for selecting subsets of patients at increased risk for local recurrence who can most benefit from radiation treatment.
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by mammography-Review of 1182 consecutive histologically confirmed cases. Eur J Cancer 30A:40, 1994 14. Clark RM, Whelan T, Levine M, et al: Randomized clinical trial of breast cancer irradiation following lumpectomy and axillary dissection for node-negative breast cancer: An update. J Natl Cancer Inst 88:1659, 1996 15. Cocconi G, DiBlasio B, Alberti G, et al: Problems in evaluating response of primary breast cancer to systemic therapy. Breast Cancer Res Treat 4309, 1984 16. Crile G Jr, Esselstyn CB Jr: Factors influencing local recurrence of cancer after partial mastectomy. Cleveland Clin J Med 57143, 1990 17. Cuzick J, Steward H, Peto R, et al: Overview of randomized trials of postoperative adjuvant radiation therapy. Cancer Treatment Reports 71:15, 1987 18. DeLena M, Varini M, Zucali R, et al: Multimodal treatment for locally advanced breast cancer: Results of chemotherapy-radiotherapy versus chemotherapy-surgery. Cancer Clinical Trials 4:229, 1981 19. Dershaw DD: Mammographic detection of breast cancer and preoperative needle localization. Semin Surg Oncol 7:247, 1991 20. Dufy SW, Tabar L, Fagerberg G, et al: Breast screening, prognostic factors and survival. Results from the Swedish Two County study. Br J Cancer 64:1133, 1991 21. Early Breast Cancer Trialists’ Cooperative Group: Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials. N Engl J Med 333:1444, 1995 22. Ebbs SR, Yamold J R Patient and anatomical selectivity in post-operative radiotherapy for early breast cancer: A British prospective. Semin Surg Oncol 8:167, 1992 23. Eusebi V, Feudale E, Foschini M, et al: Longterm follow-up of in situ carcinoma of the breast. Semin Diagn Pathol 11:223, 1994 24. Feldman L, Hortobagyi G, Buzdar A, et al: Pathological assessment of response to induction chemotherapy in breast cancer. Cancer Res 46:2578, 1986 25. Fentiman IS, Poole C, Tong D, et al: Inadequacy of iridium implant as sole radiation treatment for operable breast cancer. Eur J Cancer 32A5608, 1996 26. Fentiman IS, Poole C, Tong D, et al: Iridium implant treatment without external radiotherapy for operable breast cancer: A pilot study. Eur J Cancer 27447, 1991 27. Fisher 8, 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 radiation in the treatkent-of breast cancer.-N Engl J Med 333:1456, 1995 28. Fisher B, Dignam J, Wolmark N, et al: Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 16:441, 1998 29. Fisher ER, Constantino J, Fisher B, et al: Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-17. Intraductal carcinoma (ductal carcinoma in situ). Cancer 75:1310, 1995 30. Fisher ER, Saas R, Fisher B, et al: Pathological findings from the National Surgical Adjuvant Breast Project (Protocol 6): Relation of local breast recurrence to multicentricity. Cancer 571717, 1986 31. Formenti SC, Dunnington G, Uzieli B, et al: Original p53 status predicts for pathological response in locally advanced breast cancer patients treated pre-operatively with continuous infusion 5-fluorouracil and radiation therapy. Int J of Radiat Oncol Biol Phys 39:1059, 1997 32. Formenti SC, Symmans WS, Volm M, et al: Concurrent paclitaxel and radiation therapy for breast cancer. Seminars in Radiation Oncology, in press 33. Formenti SC, Lucas G, Ibarra JA, et al: Initial brachytherapy in the breast conservation approach to breast cancer. Am J Clin Oncol 18:2136, 1995 34. Forrest AP, Stewart HJ, Everington D, et al: Randomized control trial of conservation therapy for breast cancer: Six year analysis of the Scottish trial. Lancet 348:708, 1996 35. Fowble B, Hanlon AL, Fein DA, et al: Results of conservative surgery and radiation for mammographically detected ductal carcinoma in situ (DCIS). Int J Radiat Oncol Biol Phys 38:949, 1997 36. Goldhirsch A, Gelber RD, Castiglione M, et al: Relapse of breast cancer after treatment
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in premenopausal and perimenopausal women: Patterns and prognosis. J Clin Oncol 6:89, 1988 37. Haffty BJ, Fisher D, Fisher JJ: Regional nodal irradiation in the conservative treatment of breast cancer. Int J Radiat Oncol Biol Phys 195359, 1990 38. Halverson KJ, Taylor ME, Perez CA, et al: Regional node management and patterns of failure following conservative surgery and radiation therapy for Stage I and I1 breast cancer. Int J Radiat Oncol Biol Phys 26593, 1993 39. Hayman JA, Fairclough DL, Harris JR, et al: Patient preferences concerning the tradeoff between the risks and benefits of routine radiation therapy after conservative surgery for early-stage breast cancer. J Clin Oncol 15:1252, 1997 40. Herskovic A, Martz K, Al-Sarraf M, et al: Combined chemotherapy and radiotherapy compared to radiotherapy alone in patients with carcinoma of the esophagus. N Engl J Med 326:1593,1992 41. Hobar PC, Jones RC, Shouten J, et al: Multimodality treatment of locally advanced breast cancer. Arch Surg 123:951, 1988 42. Holland R, Veling SHJ, Mravunac M, et al: Histological multifocality of TIS, T1-2 breast carcinomas: Implications for clinical trials of breast-conserving surgery. Cancer 56:979, 1985 43. Holmes FA, Valero V, Walters J, et al: The MD Anderson Cancer Center experience with Taxol in metastatic breast cancer. Monographs National Cancer Institute 15:161, 1993 44. Hortobagyi GN, Blumenschein GR, Spanos W, et al: Multimodal treatment of locoregionally advanced breast cancer. Cancer 51:763, 1983 45. Hoskin PJ, Rajan B, Ebbs S, et al: Selective avoidance of lymphatic radiotherapy in the conservative management of early breast cancer. Radiother Oncol25:83, 1992 46. Joensuu H, Toikkanen S: Prognosis of breast cancer with small primary tumour. Acta Oncol 30:793, 1991 47. Kandioler-Eckersberger D, Taucher S, Steiner B, et al: p53 genotype and major response to anthracyclin or paclitaxel-based neoadjuvant treatment in breast cancer patients [abstract 3921. Proceedings of the 34th Annual Meeting of the American Society of Clinical Oncology. Los Angeles, May 1619, 1998 48. Kauffmann M, Jonar W, Abel U, et al: Adjuvant randomized trial of doxorubicin/ cyclophosphamide versus doxorubicin/ cyclophosphamide / tamoxifen and CMF chemotherapy versus tamoxifen in women with node positive breast cancer. J Clin Oncol 11:454, 1993 49. Kinne DW, Petrek JA, Osborne MP, et al: Breast carcinoma in situ. Arch Surg 124:33, 1986 50. Kuske RR, Bolton JS, Wilenzick RM, et al: Brachytherapy as the sole method of breast irradiation in TIS, T1, T2, NO-1 breast cancer. Int J Radiat Oncol Biol Phys 30(S1):245, 1994 51. Lagios MD, Westdahl PR, Rose MR: The concept and implications of multicentricity in breast carcinoma. Pathol Annu 16:83, 1991 52. Lagios MD, Westdahl PR, Margolin FR, et al: Duct carcinoma in situ: Relationship of extent of noninvasive disease to the frequency of occult invasion, multicentricity, lymph node metastases, and short-term treatment failures. Cancer 50:1309, 1982 53. Lagios MD: Ductal carcinoma in situ: Controversies in diagnosis, biology, and treatment. The Breast Journal 1:68, 1995 54. Lau DH, Ryu JK, Gandara DR, et al: Twice-weekly paclitaxel and radiation for stage I11 non-small cell lung cancer. Semin Oncol 24:(4 Suppl 12):S12-106, 1997 55. Liebmann J, Cook JA, Fisher J, et al: In vitro studies of taxol as radiation sensitizer in human tumor cells. J Natl Cancer Inst 86:441, 1994 56. Liligren G, Holmberg L, Adami H, et al: Sector resection with or without postoperative radiotherapy for stage I breast cancer. A randomized trial. J Natl Cancer Inst 82:277, 1990 57. Lippman ME, Sorace RA, Bagley CS, et al: Treatment of locally advanced breast cancer using primary induction chemotherapy with hormonal synchronization followed by radiation therapy with or without debulking surgery. National Cancer Institute Monographs 1:153, 1986
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58. McArdle CS, Crawford D, Dykes EH, et al: Adjuvant radiotherapy and chemotherapy in breast cancer. Br J Surg 73:264, 1986 59. McCormick B, Rosen PP, Kinne D, et al: Duct carcinoma in situ of the breast: An analysis of local control after conservative surgery and radiotherapy. Int J Radiat Oncol Biol Phys 21:289, 1991 60. Merajver SD, Weber EL, Cody R, et al: Breast conservation and prolonged chemotherapy for locally advanced breast cancer: The University of Michigan experience. J Clin Oncol 15:2873, 1997 61. Milas L, Hunter N, Kurdoglu EL, et al: Kinetics of mitotic arrest and apoptosis in murine mammary and ovarian tumors treated with taxol. Cancer Chemotherapy and Pharmacology 35:297, 1995 62. Milross C, Mason K, Hunter N, et al: Relationship of mitotic arrest and apoptosis to antitumor effect of paclitaxel. J Natl Cancer Inst 88:1308, 1996 63. Mittra I, MacRae DK A meta-analysis of reported correlations between prognostic factors in breast cancer: Does axillary lymph node metastasis represent biology or chronology? Eur J Cancer 12:1574, 1991 64. Morris AD, Morris RD, Wilson JF, et al: Breast conserving therapy versus mastectomy in early-stage breast cancer: A meta-analysis of 10 year survival. Cancer Journal from Scientific American 3:6, 1997 65. Muss HB, Thor AD, Berry DA, et al: c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med 330:1260,1994 66. Nabholtz JM, Gelmon K, Bontenbal M, et al: Randomized trial of two doses of paclitaxel in metastatic breast cancer. J Clin Oncol 141858, 1996 67. Overgaard M, Hansen SP, Overgaard J, et al: Postoperative radiotherapy in high risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 337949, 1997 68. Palda VA, Llewllyn-Thomas HA, Mackenzie RG, et al: Breast cancer patients' attitudes about rationing post-lumpectomy radiation therapy: Applicability of trade off methods to policy-making. J Clin Oncol 15:3192, 1997 69. Parker SL, Tong T, Bolden S, et al: Cancer statistics 1996. CA Cancer J Clin 46:5, 1996 70. Paszat LF, Mackillop WJ, Groomer PA, et al: Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology and end-result cancer registries. J Clin Oncol 16:8, 1998 71. Perloff M, Lesnick GJ, Korzun A, et al: Combination chemotherapy with mastectomy or radiotherapy for stage I11 breast carcinoma: A Cancer and Leukemia Group B study. J Clin Oncol 6:261, 1988 72. Perry MC, Eaton WL, Propert KJ, et al: Chemotherapy with or without radiation therapy in limited small cell carcinoma of the lung. N Engl J Med 316:912, 1987 73. Pierce LJ, Lippman M, Ben-Baruch N, et al: The effect of systemic therapy on localregional control in locally advanced breast cancer. Int J Radiat Oncol Biol Phys 23:949, 1992 74. Ragaz J, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in nodepositive premenopausal women with breast cancer. N Engl J Med 337956, 1997 75. Recht A, Bartelink H, Forquet A, et al: Post-mastectomy radiotherapy: Questions for the twenty-first century. J Clin Oncol 16:8, 1998 76. Roelofsen F, Bosset JF, Eschwege F, et al: Concomitant radiotherapy and chemotherapy superior to radiotherapy alone in the treatment of locally advanced anal cancer: Results of a phase I11 randomized trial of the EORTC Radiotherapy and Gastrointestinal Cooperative Groups. Proceedings of the American Society b i Clinical Oncology 14:194, 1995 77. Rosen PP, Fracchia AA, Urban JA, et al: "Residual" mammary carcinoma following simulated partial mastectomy. Cancer 35:739, 1975 78. Rosner D, Bedwani RN, Vana J, et al: Noninvasive breast carcinoma: Results of a national survey by the American College of Surgeons. Ann Surg 192:139, 1980 79. Rubens RD: Management of early breast cancer. BMJ 304:1361, 1992 80. Schwartz GF, Finkel GC, Garcia JC, et al: Subclinical ductal carcinoma in situ of the breast: Treatment by local excision and surveillance alone. Cancer 70:2468, 1992 81. Schwartz GF, Birchansky CA, Komarnicky LT, et al: Induction chemotherapy followed
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by breast conservation for locally advanced carcinoma of the breast. Cancer 73:362, 1994 82. Shaake-KoningC, Van den Bogaert W, Dalesio 0, et al: Effects of concomitant cisplatin and radiotherapy on inoperable non small cell lung cancer. N Engl J Med 326:524,1992 83. SilversteinMJ, Cohlan BF, Gierson ED, et al: Duct carcinoma in situ: 227 cases without microinvasion. Eur J Cancer 28:630, 1992 84. Silverstein MJ, Lagios MD, Craig PH, et al: A prognostic index for ductal carcinoma in situ of the breast. Cancer 77:2267, 1996 85. Sneige N, McNeese MD, Atkinson EN, et ak Ductal carcinoma in situ treated with lumpectomy and irradiation: Histopathologic analysis of 49 specimens with emphasis on risk factors and long term results. Hum Pathol26:642, 1995 86. Solin LJ, Kurtz J, Forquet A, et al: Fifteen-year results of breast-conserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast. J Clin Oncol14754, 1996 87. Solin LJ, Yeh I, Kurtz J, et ak Ductal carcinoma in situ (intraductal carcinoma) of the breast treated with breast-conserving surgery and definitive irradiation. Correlation of pathologic parameters with outcome of treatment. Cancer 71:2532, 1993 88. Solin LJ, McCormick B, Recht A, et al: Mammographically detected, clinically occult ductal carcinoma in situ (intraductal carcinoma) treated with breast conserving surgery and definitive breast irradiation. The Cancer Journal from Scientific American 2:158, 1996 89. Sounders DE, Lawrence DW, Christensen C, et al: Paclitaxel-induced apoptosis in MCF-7 breast cancer cells. Int J Cancer 70214, 1997 90. Steinberg L, Hassan M, Olmsted L, et al: A phase I trial of radiotherapy and simultaneous 24-hour paclitaxel in patients with locally advanced head and neck squamous cell carcinoma. Sem Oncol24 (Suppl 19):S19-51, 1997 91. Stotter A, Atkinson EN, Fairston BA, et ak Survival following locoregionalrecurrence after breast conservation therapy for cancer. Ann Surg 212166, 1990 92. SunshineJA, Moseley MS, Fletcher WS, et al: Breast carcinoma in situ: A retrospective review of 112 cases with a minimum 10 year follow-up. Am J Surg 150:44, 1985 93. Swain SM, Sorace RA, Bagley CS, et al: Neoadjuvant chemotherapy in the combined modality approach of locally advanced non-metastatic breast cancer. Cancer Res 473889, 1987 94. Theriault R, Buzdar AU, Hortobagyi GN, et al: Irradiation (XRT) following mastectomy in patients treated with FAC adjuvant therapy [abstract 3811. Proceedings of the 34th Annual Meeting of the American Society of Clinical Oncology. Los Angeles, May 16-19, 1998 95. Touboul E, Buffat L, Lefranc p, et ak Possibility of conservative local treatment after combined chemotherapy and preoperative irradiation for locally advanced noninflammatory breast cancer. Int J Radiat Oncol Biol Phys 341019, 1996 96. Tubiana M, Holland R, et al: Commission of the European Communities “Europe Against Cancer” Programme. European School of Oncology Advisory Report. Management of non-palpable and small lesions found in mass breast screening. Eur J Cancer 30A:538, 1994 97. Van Limbergen E, Rijnders A, van der Schueren E, et ak Cosmetic evaluation of breast conserving treatment for mammary cancer. 2. A quantitative analysis of the influence of radiation dose, fractionation schedule and surgical treatment techniques on cosmetic results. Radiother Oncol 16253, 1989 98. Velez-Garcia E, Carpenter JT, Moore M, et ak Post-surgical adjuvant chemotherapy with or without radiotherapy in women with breast cancer and positive axillary nodes: A South-Eastern Cancer Study Group (SEG) trial. Eur J Cancer 28A1833,1992 99. Veronesi U, Luini A, Del Vecchio M, et ak Radiotherapy after breast preserving surgery in women with localized breast cancer. N Engl J Med 3821587, 1993 100. Vicini F, Chen P, Benitez P, et ak Irradiation of the tumor bed alone after lumpectomy in selected patients with early breast cancer treated with breast conserving therapy: Preliminary results of a pilot trial. Int J Radiat Oncol Biol Phys 39293, 1997 101. Wahl AF, Donaldson KL, Fairchild C, et ak Loss of normal p53 function confers sensitization to taxol by increasing G2/M arrest and apoptosis. Nat Med 272,1996
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102. Wazer DE, Erban JK, Robert NJ, et a1 Breast conservation in elderly women for clinically negative axillary lymph nodes without axillary dissection. Cancer 74878, 1994 103. Wong JS, Nixon AJ, Recht A, et al: Treatment outcome after tangential radiotherapy alone without axillary dissection in patients with early stage breast cancer with clinically negative axillary nodes. Int J Radiat Oncol Biol Phys 36:215, 1996 104. Woods CM, Zhu J, McQueney PA, et al: Taxol-induced mitotic block triggers rapid onset of a p53-independent apoptotic pathway. Mol Med 1:506, 1995 105. Zellars R, Clark GM, Allred DC, et al: Prognostic value of p53 for local failure in mastectomy treated breast cancer patients [abstract 4011. Proceedings of the 34th Annual Meeting of the American Society of Clinical Oncology. Los Angeles, May 1619. 1998
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0889-8588/99 $8.00
+ .OO
AN UPDATE ON RADIATION THERAPY IN BREAST CANCER Silvia Formenti, MD, and Garth Green, MD
Radiation therapy plays an important role in the management of both invasive and noninvasive breast cancer. During the last 20 years, the availability of radiation therapy has made it possible to test the feasibility and safety of breast preservation after the diagnosis of earlystage breast cancer. Two recent meta-analysesZ1,63 of prospective randomized trials comparing mastectomy to breast preservation and radiation have demonstrated the equivalence of the two modalities in terms of local control and overall survival. Further, one of the meta-analyses has detected that patients with node-positive disease who underwent breast preservation had a survival advantage compared with the mastectomy arm.63Despite this evidence, in the United States less than half the patients eligible for breast preservation surgery receive such treatment. At least in some cases, the fact that radiation therapy is required after partial mastectomy affects the decision about mastectomy versus breast preservation. Many patients maintain a deep-rooted fear of radiation. In some places radiation therapy facilities are not easily accessible. Because the conventional postoperative course of radiation requires daily attendance (Monday to Friday) for 5 to 6 weeks, it is often perceived as a major inconvenience. Most recently, attempts were made to question critically whether, at least in some subsets of patients with carcinoma in situ or with early-stage breast cancer, radiation could be modified or omitted after segmental mastectomy. At the same time, recent data from
From the Kenneth Norris Jr Cancer Center, University of Southern Califomia, Los Angeles, California HEMATOLOGY/ ONCOLOGY CLINICS OF NORTH AMERICA
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two randomized trials have re-opened the option of adding radiotherapy after mastectomy, at least in patients with node-positive disease. Finally, the conventional locoregional approach to locally advanced breast cancer is also under scrutiny, and studies are ongoing to test safety and feasibility of breast preservation with radiation instead of modified radical mastectomy. This article summarizes some of the ongoing controversies concerning the use of radiation therapy in the multidisciplinary management of breast cancer.
THE ROLE OF RADIATION THERAPY IN THE BREAST CONSERVATION APPROACH TO CARCINOMA IN SlTU The rate of breast cancer detection has accelerated because of the ability of mammography to identify small, nonpalpable breast lesions. The utilization of mammography may be capable of diminishing mortality by as much as 40% in the postmenopausal population, for whom mammographic imaging is most accurate. Mass mammography screening has resulted in large numbers of suspicious nonpalpable lesions being biopsied. Although most lesions biopsied are benign, approximately 10% to 30% of those excised at any institution are found to be malignant.13,l9 Now, approximately 13%of newly diagnosed breast cancers are ductal carcinoma in situ (DCIS),69compared with 2% in 1980, when most DCIS were diagnosed either as a palpable mass, because of bloody nipple discharge, or as an incidental finding in a biopsy performed for other reasons.7* By definition, DCIS represents a proliferation of malignant cells confined to the ductal system without evidence of invasion into the basement membrane on light microscopy. Strictly speaking, there is no risk of regional or distant dissemination. The ultimate risk of mortality from this lesion, then, is related to the concomitant presence or development of an invasive breast cancer with its attendant risk of distant metastases. Preventing this development is the major issue in the management of DCIS. Multiple options are available for women with DCIS, including a wide excision, wide excision with radiation, or mastectomy. In evaluating these different approaches, one must assess the risk of an ipsilateral invasive or noninvasive breast recurrence, the effect and prognosis of such a recurrence, and, ultimately, the risk of death secondary to breast cancer. Although mastectomy offers high rates of local regional control (96%-100%) and cause-specific survival (96%-100%), it seems radical, especially when early-stage invasive cancers can be treated with breast
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c~nservation.~~, 92 Therefore, breast-preserving approaches that include wide excision with or without radiation have been investigated. Currently, the biggest controversy centers around which patients may be successfully treated with excision alone. In most series of wide excision alone, patients are highly selected for small, nonpalpable masses diagnosed by microcalcifications at mammography, making direct comparisons to radiated patients sometimes difficult. For instance, in Lagios and colleagues’ seminal series of patients treated with wide excision only, eligible patients had DCIS which was a mammographically detected area of microcalcifications measuring 25 mm or less with negative resection margins and negative postbiopsy rnamm~grarn.~~ In a recent update, Lagios reported a 17% rate of breast cancer recurrence with a median follow-up of approximately 10 years.52Other investigators have presented similar results.u, In general, recurrence rates are correlated with the method of detection of the original DCIS and its histologic features: a palpable mass, high nuclear grade, comedo histology, and presence of necrosis are poor prognostic featuresm6 Approximately half these recurrences will be invasive, and almost all will be in the same region as the initial lesion. Salvage rates are good for both noninvasive and invasive recurrences, being close to 100% and approximately 75%, respectively. In an alternative approach analogous to that applied in early-stage invasive disease, radiation has been delivered after wide excision for DCIS. Selection factors are less strict than those applied by Lagios et al, making more patients potentially eligible for breast preservation. Crude rates of breast cancer recurrence range from 0% to l8%, with causespecific survivals of 96% to 59, 86, 88 Solin and colleagues reported the results of 268 women treated with excision and irradiation at 10 institutions in the United States and Europe. At a median follow-up of 10.3 years, there were 45 ipsilateral breast cancer recurrences. The 15year actuarial breast cancer recurrence rate was 19%, and the 15-year actuarial cause-specific survival was 96%. Median time to failure was 5.2 years.86 Failure to remove residual calcifications on postbiopsy mammogram has resulted in a high risk of breast cancer recurrence in the small numbers of patients reported.59,85 The effects of other clinical factors, including bloody nipple discharge, age, and family history, are inconclusive from available data. The influence of pathologic features on breast cancer recurrence has also been The collaborative group identified an increased risk of failure for high nuclear grade, comedo carcinoma at 8 years.86,87 With further follow-up, however, these factors were no longer significant, reflecting only a difference in the median interval to breast cancer recurrence, the intervals being 3.1 years for high nuclear grade, comedo carcinoma and 6.5 years for the low grade or
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noncomedo DCIS.86Silverstein and associates reported similar findings, suggesting that series with short follow-up will overestimate the effect of high grade or comedo histology on recurrence rates.83Recent reports also suggest that wide excision with negative microscopic margins is extremely important in reducing the risk of breast cancer recurrence.29, 85, Silverstein and associates have proposed a treatment algorithm that uses tumor size, margin width, and nuclear grade/necrosis to predict breast cancer recurrence ~ates.8~ In Silverstein's retrospective series, irradiated patients who had negative margins, low / intermediate grade tumors, and no necrosis had similar risk of an invasive recurrence, similar patterns of breast cancer recurrence, and similar rates of salvage to those of patients treated with excision alone. Although this classification may help select appropriate patients for breast conservation, its validity must be confirmed by other data sets and, ideally, tested by a prospective randomized trial. At the present time, the available alternatives remain mastectomy or segmental mastectomy followed by whole-breast radiation.
CONTROVERSIES IN THE MANAGEMENT OF POSTMENOPAUSAL WOMEN WITH T1 CANCERS
Another effect of the implementation of mammographic screening is the emergence of a new patient population: postmenopausal women with nonpalpable tumors, detected at routine mammography and frequently measuring less than 2 cm (i.e., T1 tumors at TNM staging). The natural history of these tumors is not well known because data are scarce, and there is no general agreement on the method used for measuring the volume. Because of this lack of information, controversy exists regarding the correct management of these patients. For instance, the need for axillary node dissection has been questioned because, among invasive cancers of this size, lymph-node involvement is rarely observed: the incidence in pTla (0.5 cm or less in greatest dimension) is O%, pTlb (more than 0.5 cm but less than 1 cm in greatest dimension) is 7%, pTlc (more than 1 cm and less than 2 cm) is 13%.2,13,96 Moreover, nodal status is an imperfect predictor of the risk for systemic relapse.2o,46. 63, 96 In most cases the main role of axillary dissection is to guide the choice of adjuvant systemic therapy. Consequently, the role of axillary node dissection is controversial for postmenopausal women with T1 cancers who will, in any case, be treated with adjuvant tamoxifen, as supported by the significant benefit recognized by the meta-analysis of adjuvant treatments? These considerations have significance because of the reported potential long-term morbidities of axillary node dissection, including lymphedema, chronic shoulder
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pain, and hypoesthesia. During the last few years many breast cancer centers have adopted the policy of sparing axillary node dissection to postmenopausal women with Tla and Tlb primary tumors. Some investigators have advocated radiation to the axilla as a substitute for surgical dissection.37,lo2 For instance, with a median follow-up of 54 months, Wazer et a1 found no regional nodal recurrences among 94 postmenopausal breast cancer patients who had undergone breast and regional node radiation.lo2Moreover, four studies of selected postmenopausal women with cancers measuring less than 1 cm who were spared axillary dissection or radiation have reported axillary recurrence rates of 0% to 7%.22,38, 45, lo3The authors believe that treatment guidelines should be determined and implemented nationally. At this time, the management of the axilla needs to be discussed with each patient, and a careful description of the risk/ benefit ratio must be provided. Another area of controversy relates to the issue of whether wholebreast radiation therapy is necessary for this patient subset.'" 56, 79, 91, 99 Originally, the Cleveland Clinic reported an incidence of local recurrence of 10.9% among a series of women who had undergone breast-preserving surgery only.16 This rate is quite different than that found in a prospective randomized trial by the National Surgical Adjuvant Breast and Bowel Project (NSABP-06) at 12 years in which there was a local recurrence rate of 35% in the women receiving segmental mastectomy alone, compared with 10% in the women who also received r a d i a t i ~ n . ~ ~ The NSABP-06 incidence is consistent with the findings from pathology series. Holland et a1 elegantly documented the incidence of multifocality/ multicentricity among small breast cancers. For lesions measuring 2 cm in diameter or smaller, other microscopic foci (including lymphatic emboli) of invasive cancer outside a 2 cm margin from the primary tumor were detected in 14% of the specimens.a These rates are similar to those reported by other authors30,51 and by Rosen et al, who analyzed 203 mastectomy specimens and identified multicentricity in 26% of the breasts with index lesions measuring less than 2 cm and in 36% among those with index lesions measuring more than 2 and less than 4 cm.77 Results from five prospective randomized trials are available to clarify this issue (Table 1). Although these studies differ in their criteria for patient eligibility, type of surgery, and duration of follow-up, they are consistent in confirming superior local control when radiation is added to surgery. More can be learned by carefully analyzing each study. The study conducted at the Netherlands Cancer Institute randomized 381 T1 breast cancer patients (including both premenopausal and postmenopausal women) to sector resection with or without radiation. Predictably, at 5-year follow-up, a significantly higher rate of local recurrence occurred in the arm receiving segmental mastectomy alone (18.4%)
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Table 1. PROSPECTIVE RANDOMIZEDTRIALS OF BREAST-PRESERVING SURGERY WITH OR WITHOUT ADJUVANT RADIATION THERAPY ~
Author (Re9
Fisher (27) Clark (14) Forrest (34) Veronesi (99) Liligren (56)
Number Cancer of Size Patients (cm)
1362 837 585 567 381
4
4 4 4
2
+
Type of Surgery
Local Resection Surgery Alone
wide excision wideexcision wide excision quadrantectomy sectorresection
35 35 25
9 18
Surgery Radiation Therapy
10 11 6 C1
2
Follow-up (years)
12 7.5 6 3.5 6
compared with the arm receiving segmental mastectomy and postoperative radiotherapy (2.3%).Noticeably 77% of the recurrences in the surgery-alone arm occurred within the initial tumor bed. The findings suggest that adjuvant radiation to a volume inclusive of the tumor with sufficient margins might be adequate to affect significantly the risk of local recurrence among women with a particularly low risk. For instance, in this study all patients carried tumors measuring less than 2 cm that were removed with generous margins (sector resection). It would be particularly interesting to investigate a reduction of the target volume of radiation, both to decrease exposure of normal tissue and to explore This area of research should more convenient fractionation study women who are predicted to carry the lowest risk of recurrence: women with completely excised T1 tumors who are older than 55. The study from Veronesi and co-workers seems to corroborate the finding of the Netherlands Cancer Institute. Veronesi et a1 employed a more extensive surgical procedure that allows larger excisional margins (quadrantectomy)and found no additive benefit by adding radiotherapy postquadrantectomy in women older than 55.% Since in the United States breast-preservation surgery is mostly tylectomy a form of segmental mastectomy that achieves less generous margins than quadrantectomy and results in better cosmetic outcome, adjuvant radiotherapy to the tumor bed could compensate for less extensive surgery. Several investigators have explored the use of brachytherapy directed to the tumor bed, without external irradiation to the rest of breast tissue. These pilot studies have demonstrated feasibility, but long-term data on local control are not available yet.25,26* 33,97, looThe Radiation Therapy Oncology Group (RTOG) is conducting a multi-institutional study of brachytherapy alone after segmental mastectomy. Although the technique has been shown to be quite effective in breast cancer and requires only 5 to 7 days of treatment, it is invasive and, if low dose rate brachytherapy is prescribed, it demands the patient's isolation during radioactive treatment. Moreover, long-term cosmetic results are not yet available, and the risk of
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fibrosis and induration at the implant site remains a concern, especially since it impairs routine physical examination of the breast.33,97
UPDATE OF POSTMASTECTOMY RADIATION THERAPY
The recent reports from two prospective randomized trials of mastectomy with and without radiation have re-opened the discussion of the effect of local control on the ultimate survival from breast cancer.67, 74 Previous studies had provided evidence that optimization of local control produces small improvements in overall survival, at least among some patient subsets.', 5, 58, 98 The two more recent studies from Danish and Canadian investigators have become the central subject of tumor boards and interdisciplinary conferences all over the country. The pertinent discussion can be structured by asking several consecutive questions. First, are the findings of the Canadian and Danish studies translatable to the ongoing practice of breast oncology in United States? Most breast cancer centers in the United States will challenge the adequacy of the axillary dissection received by the patients in these two series. Because most of the women in the series had undergone less extensive axillary staging, it is possible that at least to a certain extent some stage-shift phenomenon could account for a regional recurrence rate of approximately 30% detected in these two studies, compared with the standard rates in the United States of 6% to 13%. In other words, reduced surgical staging could underestimate the actual nodal involvement so that patients are understaged. This possibility is reinforced because, when compared with published series of studies in the United States, more nodal recurrences were detected in each nodal subset (both for patients with one to three and for those with four or more involved nodes).&12. 36, 48. 98 At present the issue remains open, as it is quite possible that the addition of nodal radiation could have compensated for potentially suboptimal surgical management of the axilla. To complicate the question, the radiation techniques employed in both studies are now seldom used in the United States, where internal mammary nodes are not electively included in most post-mastectomy radiation protocols. This difference makes comparison of the Danish and Canadian series with United States radiation series impossible. For instance, in a recently reported retrospective analysis of the experience at the M. D. Anderson Cancer Center, the risk of local recurrence was reduced from 11%in patients receiving 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) alone to 5.6% in patients receiving FAC plus radiation therapy. No difference in survival was found, probably because most patients
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were selected to receive radiation based on their estimated increased risk for local r e c ~ r r e n c e . ~ ~ Finally will the survival advantage detected remain at 20-years follow-up? A previous meta-analysis of radiation trials detected a breast cancer cause-specific survival advantage of 3% at 10 years accompanied by a 2% increased hazard of mortality from other causes, resulting in a nonsignificant overall benefit.17 It is possible that the findings of the Danish and Canadian studies represent the early results achieved by adding radiotherapy in a subset of women at increased risk; whether the use of modern radiation techniques in these trials would prevent long-term increased cardiac mortality among these women remains 70
How, then, to make best use of the information provided by the Canadian and Danish studies? Who are the patients who should undergo adjuvant radiation therapy and should the same radiation techniques be adopted? As eloquently pointed out by Recht et a1 in a recent editorial in the Journal of CZinicuZ OncoZogy, it is likely that, as is also reported for systemic therapy radiation therapy generates relatively consistent proportional risk reductions among different patients The question becomes at what point absolute risk should be considered sufficient to justify the potential morbidity and cost of adjuvant radiation. Although studies conducted among patients undergoing breast preservation treatment suggest that even a small reduction in risk of local recurrence is sufficient to justify radiation treatment for most women,39, a recent report demonstrated an increased risk of cardiovascular disease in patients with cancer in the left breast who had received adjuvant ~ a d i a t i o n ,so ~ ~that all efforts to shield the heart from the radiation ports are warranted. At this time these issues and their precise implications must be explained and discussed with patients. The American Society of Clinical Oncology (ASCO) has appointed an expert panel to review the existing published information and to design guidelines for postmastectomy radiotherapy that will be available to the public in 1999. CHEMORADIATION IN LOCALLY ADVANCED BREASTCANCER
Originally pioneered by DeLena and co-workers in Europe and by the M. D. Anderson Cancer Center in this country, the paradigm of primary or neoadjuvant chemotherapy followed by surgery, followed by prophylactic radiotherapy, has been extensively tested in locally advanced breast cancer (LABC).I0,Is, a 41, * 57, 93 These studies have proven the feasibility of sequential multimodality therapy. Local control rates in
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the range of 54% to 85% are obtained and are superior to those achieved in historical controls by radiation or surgery alone or by the combination of the two. Five-year survival rates of approximately 55% are achieved for the entire group of LABC patients, but, at subset analysis, stage IIIA consistently fares better than stage IIIB, with 5-year survival rates of 84% and 44%, respectively.44 What is the ideal local management after primary chemotherapy? It appears that in LABC no significant survival advantage is associated with the addition of mastectomy compared with a noninvasive local management by radiation therapy. The original study by DeLena et a1 of 132 women with LABC consisted of three cycles of vincristine and doxorubicin followed by randomization to radiation or surgery. No differences in disease-free survival or overall survival were found between the two arms.lSThe same results were obtained in a more recent study from the Cancer and Leukemia Group B (CALGB) which randomized 87 stage I11 patients after chemotherapy to either surgery or radiation. Although a higher local recurrence rate was identified in the radiation arm (27% versus 190/,),the rate of distant metastases was identical for both arms (25%) and, with a median follow-up of 37 months, there was no difference in survival between the two groups.71Finally, Buzdar et a1 found no difference in the rate of local recurrence when surgery was added to radiotherapy; however, the combination of the two modalities allowed a reduction in the radiation dose, resulting in less radiationinduced morbidity.l0 Encouraged by these data, several more recent clinical trials of LABC have been designed with the endpoints of both breast preservation and survival. With careful patient selection (based on the clinical and radiological response to primary therapy), 5-year local control is approximately 85% to 90%. When the entire series of LABC is analyzed (including patients deemed noneligible for breast preservation), 5-year breast-preservation rates of approximately 52% to 77% are achieved.l5> 60, 73, 95 Unfortunately, clinical evaluation of residual tumor does not reliably predict for pathological response: approximately one third of LABC patients found to have pathological clearance of tumor cells after primary treatment have residual palpable masses at physical examination, and a similar proportion of patients with clinical complete response have persistent disease in the pathology specimen.lO, 15,44, 60, 73, 95 Numerous noninvasive techniques to assess clinical response more accurately after primary chemotherapy are under investigation. Concurrent Chemoradiation: The University of Southern California Experience Since 1993 the University of Southern California (USC) interdisciplinary breast cancer group has followed a paradigm of clinical research
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that tests preoperative concurrent chemoradiation in LABC. The extent of the pathological response of the primary tumor is used as an endpoint to measure tumor resistance to the tested combination. The rationale behind this model is many-fold. First, the encouraging results achieved by concurrent chemoradiation in other tumor models have motivated the testing of this approach in LABC.S n,76 Second, this subset of women is generally at high risk for tumor persistence/local recurrence after chemotherapy and surgery, and their management must always include radiation therapy. Moreover, because it is easily biopsied, LABC is an excellent model for translational research. Tumor specimens obtained before treatment can be analyzed for potential markers that predict for response to the tested regimens, and biological profiles of the primary tumor are prospectively acquired for each patient studied. Associations of the markers tested with the extent of pathological response of the primary tumor can be explored to generate hypotheses to explain mechanisms of tumor resistance to the tested regimen. The first study of concomitant chemoradiation conducted at USC consisted of continuous infusion (c.i.) fluorouracil (5-FU) and concomitant radi~therapy.~~ The combination showed a synergistic effect in converting to resectability with primary wound closure all 35 originally inoperable patients. Clinical response (complete response [CR] plus partial response [PR]) measured by the interdisciplinary team 1 to 2 weeks before mastectomy was 72%. Pathological complete response (pCR) was defined as the clearance of invasive cancer in the breast and axillary contents. Pathological partial response (pPR) consisted of persistence of fewer than 10 microscopic foci of invasive tumor cells in the breast or in the axillary contents; a lack of pathological response (pNR) included any larger number of residual cancer cells in the breast or in the axillary contents. Persistence of DCIS was accepted and did not modify this classification for invasive disease. Pathological complete clearance of invasive tumors occurred in 7 of 35 patients (20%),and 5 other patients had only microscopic residual cancer (pCR + pPR = 34%), a remarkably high rate among this population of locally advanced, inoperable breast cancer As others have also reported no correlation was found between clinical response and pathological re~ponse,'~, n, 95 supporting caution in adopting breast-preservation protocols in this subset of women. Probably the most important result of this study is the preliminary evidence of the association of p53 status with pathological response. As part of the study design, all patients underwent pretreatment core biopsies of the primary tumor and a second core biopsy after 2 weeks of c.i. FU alone before combining radiation. The specimens were evaluated at immunohistochemistry for expression of the p53 protein product, HER2/neu and thymidylate synthase. Eleven of 21 patients (52%) with no evidence of p53 overexpression at immunohistochemistry (anindirect
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evidence for lack of mutation of the p53 gene) achieved a pathological response to the regimen, compared with 1 of 14 patients (7%) with overexpressed p53 ( P = 0.010).31At multivariate analysis, lack of p53 overexpression was the only independent prognostic factor for pathological response. This pilot study provided preliminary evidence for potential patient selection to a specific treatment for LABC. However, since most patients who overexpressed p53 failed to achieve a pathological response, it became important to investigate the use of drugs that may be differently affected by p53 status. Taxanes are indeed such lol, lo4 From the initial experience of concomitant FU and radiation, a study was designed of twice-weekly paclitaxel and radiation for patients with LABC. To expedite data accrual, three academic institutions, USC, New York University (NYU), and the Mayo Clinic, Jacksonville, have joined to conduct this study. Several rationales support the testing of taxanes and specifically studying paclitaxel. Paclitaxel is a very active drug in breast cancer, producing objective response in approximately 50% to 60% of patients with advanced breast cancer when used as initial therapy, and in about 20% to 25% of patients with advanced disease resistant to other chemotherapy agents.7,9,43, 66 Budzar et a1 have reported the results of a pilot study comparing paclitaxel with cyclophosphasmide, Adriamycin, and fluorouracil (CAF) in a primary chemotherapy setting for women with operable breast cancer. Similar pathological response rates were detected in the two arms, suggesting that single-agent paclitaxel is probably equivalent to CAF in inducing pathological r e s p ~ n s eMoreover, .~ paclitaxel is a promising drug for use in combination with radiation therapy. Experience acquired in different tumor sites suggests a synergistic effect of paclitaxel with concomitant 62 possibly resulting from paclitaxel-induced accumulation of cells during the G2/M phases of the cell cycle, which are indeed the most radiosensitive phases of the cycle.61,62 An ancillary study to the clinical protocol has been designed to measure in breast cancer the kinetics of mitotic and apoptotic changes induced by paclitaxel. The preliminary data support the use of a twiceweekly schedule to exploit most effectively the paclitaxel-induced G2 / M cell accumulation during the course of radiation therapy?*
CONCLUSIONS
During the past 20 years, the applications of the findings of molecular biology to the clinical setting has revolutionized the practice of medicine. While efforts to improve the efficacy of the available treatment modalities are ongoing, another approach to increase efficacy of treatment is by better matching patients with the available treatment tools.
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In oncology, more and more attempts are being made to preselect patients for treatment by identifying tumor markers that predict for response. In breast cancer, for instance, the presence of HER2 / neu overexpression has selected a subset of tumors exquisitely sensitive to doxorubicin-based adjuvant ~hemotherapy.6~ Although indications for radiation therapy remain at this point quite general, research should focus on the identification of specific biological markers that predict for high risk of local recurrence.lo5 In addition, studies of the effects of radiation therapy on the stromal and vascular components of tumors are likely to reveal new applications for this treatment modality. Meanwhile, results from randomized trials and the use of TNM staging remain the main available tools for selecting subsets of patients at increased risk for local recurrence who can most benefit from radiation treatment.
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