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There is growing interest in the use of preoperative (neoadjuvant) chemotherapy for patients with localized breast cancer. Originally, it was hypothesized that such early use of chemotherapy might improve survival, compared with standard postsurgical adjuvant systemic therapy, but this has not proven to be the case. Nonetheless, the primary tumor response is likely a barometer for tumor sensitivity to therapy and may be used to help guide decisions regarding additional systemic therapy. Furthermore, preoperative chemotherapy can increase the fraction of women eligible for breast-conservation therapy. A seemingly logical extension of this latter observation is the hypothesis that one can further reduce local therapies in patients responding well to initial chemotherapy. For example, studies are under way to omit (or limit) radiotherapy (RT) in patients who present with positive axillary nodes and experience pathologic complete response in the nodes to preoperative chemotherapy (eg, NSABP [National Surgical Adjuvant Breast and Bowel Project] B-51/RTOG [Radiation Therapy Oncology Group] 1304). In the NSABP/RTOG study, patients with involved axillary nodes (histologically confirmed) are treated with neoadjuvant chemotherapy. Those who are node negative at subsequent mastectomy are randomly assigned to postmastectomy RT (PMRT) to the chest wall and regional nodes. Similarly, patients who undergo subsequent breast conservation surgery and whose nodes have become negative after preoperative chemotherapy will be randomly assigned to breast RT regional nodal RT. We appreciate the importance of the question being asked in these studies and support their conduct. Defining patient subgroups that do (or do not) benefit from our therapies is an important goal. It is possible that response to preoperative chemotherapy predicts for the potential benefit of local regional RT (and hence theassociatedtherapeutic ratio).Responders topreoperativechemotherapy may have a lesser need for additional local regional RT. However, we believe the converse may be true: that the potential survival benefits of local therapies are likely highest among responders to preoperative chemotherapy. Consider the more typical clinical scenario for node-positive patients who undergo initial mastectomy, followed by adjuvant chemotherapy (Fig 1). In that setting, the addition of PMRT improves overall survival (OS) by approximately 6% to 9%. This group includes both responders and nonresponders to chemotherapy, althoughidentificationofthesesubgroupsisnotpossible,becausechemotherapy is administered postoperatively. If it is true that responders to neoadjuvant chemotherapy derive lesser survival gains with PMRT, it must follow that nonresponders derive greater gains, because the OS benefit should still be 6% to 9% (ie, sequencing of surgery and chemotherapy should not alter this; Fig 1, lower panel). An analogous situation exists for patients undergoing breast conservation. The NCIC Clinical Trials Group MA.20 study reported improvements in locoregional control and distant disease-free survival and a trend in OS with the addition of nodal RT to breast RT in patients undergoing lumpectomy followed by chemotherapy. If responders to preoperative chemotherapy derive lesser gains with nodal RT, nonresponders should derive greater gains (again, to make the math work). As we discuss here, the evidence suggests that the opposite may be true: namely, that responders to systemic therapy might derive the most survival benefit from RT. Mastectomy Chemotherapy 6%-9%

The role of postmastectomy radiotherapy (PMRT) has been controversial for decades, accounting for countless presentations, debates, and papers. It was reasonably clear from the beginning that PMRT improved locoregional control. Much of the controversy has had to do with whether PMRT improved survival. The evidence is now strong that PMRT does indeed improve survival, both from individual studies and from reviews and meta-analyses. The Gebski et al analysis is particularly significant because, unlike many meta-analyses, this study controlled for the quality of the radiotherapy. The more recent studies demonstrate an absolute survival benefit of approximately 5% to 10% and approximately 66% to 75% relative reduction in locoregional recurrence. There should no longer be much doubt in the minds of oncologists as to the value of PMRT. Controversy continues to exist, however, as to the clinical characteristics of patients who would benefit significantly from PRMT. Because the risk of locoregional recurrence increases with the number of positive axillary lymph nodes, a widely adopted approach has been to apply PMRT only in patients with four or more positive axillary nodes, and not to those with one to three positive nodes. The rationale for this approach is nicely summarized in a prior Journal of Clinical Oncology editorial. If one believes that the ratio between locoregional failures avoided and breast cancer deaths prevented is approximately four to one, the group with four or more positive node group will enjoy the largest benefits in both locoregional control and survival. We have a number of concerns with this thesis, however. First, though this approach seems logical, it is not supported by the available data. In the Overgaard and Ragaz studies (Table 1), the absolute magnitude of the overall survival benefit afforded by PMRT is similar in the patients with one to three versus four or more positive lymph nodes. Many have criticized these studies for the degree of axillary surgery (median number of recovered nodes, seven in Overgaard and 11 in Ragaz), compared with a larger number of recovered nodes in some other studies. To address this criticism, a recent analysis from the Danish trials considered the subset of 1,152 node-positive patients with eight or more nodes removed (ie, median). The overall 15-year survival rate was increased by 9% in patients with either one to three positive nodes or four or more positive nodes, with a disconnect between improvement in local control and survival. Although the patients with four or more positive nodes had a far greater improvement in local control with RT than did the group with one to three nodes, the survival benefits were similar in both groups. The explanation advanced by the authors seems plausible. Improvements in locoregional control will yield survival benefits only if there is systemic tumor control as well. Because patients with four or more positive axillary nodes are likely, on average, to harbor a higher systemic subclinical disease burden than those with one to three positive nodes, improvements in locoregional control will be less likely to translate into a survival benefit in the four or more node group. Thus, the ratio between locoregional failures avoided and breast cancer deaths prevented may not be constant across patient subgroups. Further, as the efficacy of systemic therapy increases, the impact of PMRT on survival may also increase. In this regard, local and systemic therapies are synergistic rather than competitive. Second, some argue that a more complete axillary dissection would have moved most of the patients with one to three positive nodes in the Overgaard and Ragaz studies into the group with four or more positive nodes. This issue has been studied by several investigators. Danforth et al and Saha et al found that 64% to 71% of patients with one to three positive nodes after limited level I dissection (median, 10 nodes) would remain in the group with one to three positive nodes with a more complete dissection. Using mathematical models based on clinical data, Kiricute et al and Iyer et al computed that approximately 50% of patients with two positive nodes after limited dissection will remain in the group with one to three positive nodes with a more complete dissection. Thus, approximately 50% to 70% of the patients in the group with one to three positive nodes from the original Overgaard and Ragaz studies would likely remain in the same group with a more complete dissection. Thus, the often-heard suggestion that most of the patients with one to three nodes in the Overgaard and Ragaz studies would have had four or more nodes with a more complete dissection is not consistent with the data. Third, the subsetting of patients into groups with one to three versus four or more positive nodes is an artificial distinction originating in the early days of adjuvant systemic therapy for breast cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) was perhaps the first to do this, with initial benefits from adjuvant chemotherapy observed only in those with four or more positive lymph nodes. Later studies demonstrated the utility of systemic therapy in patients with one to three, or even zero, involved nodes. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 13 MAY 1 2008

1065 Background: To evaluate treatment results and prognostic factors especially margin status and molecular subtype in early stage breast cancer patients treated with breast conservation therapy (...

678 Background: Tumor oxygenation has been shown to play an important role in determining treatment resistance. However, the use of tumor oxygenation as a predictive marker has been hindered because (1) the invasiveness and time required for in vivo oxygen measurements and (2) the inability to determine tumor oxygenation on archival tissue. This study examined the relationship between endogenous hypoxia marker (carbonic anhydrase IX; CA IX) and in vivo oxygenation measurements in breast cancer. Methods: 30 patients with operable breast cancer scheduled to undergo neoadjuvant chemotherapy/hyperthermia treatment were enrolled. In vivo tumor oxygenation was performed using Eppendorf probes. Core needle biopsies were acquired at the same time as the in vivo tumor oxygenation measurements. CA IX staining was performed using the G250 murine antihuman monoclonal antibody (gift from Dr. Oosterwijk). Angiogenesis was determined using Microvessel Density counts (MVD) obtained after JC70 monoclonal antihuman CD31 an...

5089 Background: A phase I/II study of liposomal doxorubicin combined with whole abdominal hyperthermia was conducted in patients with refractory ovarian cancer. Liposomal doxorubicin combined with hyperthermia has been shown to increase liposomal extravasation into tumor xenografts resulting in enhanced cytotoxic effects. Methods: Thirty patients with either recurrent or persistent epithelial ovarian cancer were enrolled. All patients had either measurable or assessable disease. Patients received intravenous (IV) liposomal doxorubicin 40 mg/m2 as a 1-hour infusion followed by whole abdominal hyperthermia. Quality of life (QOL) was performed at baseline, prior to each cycle, and every 3 months following treatment. Results: All 30 patients were either paclitaxel and/or platinum resistant initially or developed resistant disease. The median number of prior chemotherapeutic regimens was three (range 2–8) and 6 patients had been previously treated with liposomal doxorubicin. There were 3 partial responses for...

PURPOSE: To examine the impact of consolidation radiotherapy (RT) after high-dose chemotherapy with autologous bone marrow rescue (HDC) in patients with advanced breast cancer. PATIENTS AND METHODS: Between 1988 and 1994, 425 patients with metastatic or recurrent breast cancer received doxorubicin, fluorouracil, and methotrexate (AFM) induction chemotherapy in a single-institution prospective trial. One hundred patients who achieved a complete response were randomized to receive HDC (cyclophosphamide, cisplatin, carmustine), with autologous bone marrow rescue immediately after AFM, or to observation, with HDC to be administered at next relapse. Seventy-four of the 100 became eligible for RT; 53 received consolidation RT (HDC RT+ and 21 did not (HDC RT−). The assignment of RT was not randomized. The RT+ and RT− groups were similar with regard to number of involved sites, the fraction of patients with only local-regional disease, age, and interval since initial diagnosis. Local control at previously involved sites and distant sites was assessed with extensive radiologic and clinical evaluations at the time of first failure or most recent follow-up. The impact of RT on failure patterns, event-free survival, and overall survival was evaluated. RESULTS: Sites of first failure were located exclusively at previously involved sites in 28% of RT+ patients versus 62% of RT− patients (P CONCLUSION: Patients with advanced breast cancer who were treated with HDC without RT failed predominantly at the initial sites of disease. The addition of RT appeared to reduce the failure rate at initial disease sites and may improve event-free and overall survival. Our observations await verification in a trial in which assignment to RT is randomized.