Effect of Addition of Adjuvant Paclitaxel on Radiotherapy Delivery and Locoregional Control of Node-Positive Breast Cancer: Cancer and Leuke
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▲還散笫雖悝◎
the University of North Carolina, Chapel Hill
Cancer and Leukemia Group B Statistical Center, Durham, NC
Quality Assurance Review Center, Providence, RI
Medical University of South Carolina, Charleston, SC
State University of New York Upstate Medical University, Syracuse
Memorial Sloan-Kettering Cancer Center, New York, NY
University of California San Francisco, San Francisco, CA
ABSTRACT
METHODS: Eligible patients were randomly assigned to receive adjuvant AC versus AC+T chemotherapy. RT was required if breast-conserving surgery was performed but was elective after mastectomy. Information about RT delivery was retrospectively collected. Cumulative incidence of locoregional recurrence (LRR), use of elective RT, and RT delivery were compared between treatment arms.
RESULTS: For patients treated with breast-conserving surgery and RT, the 5-year cumulative incidence of isolated LRR was 9.7% in the AC arm and 3.7% in the AC+T arm (P = .04) and of LRR as any component of failure was 12.9% versus 6.1%, respectively (P = .04). Although LRR rates in patients who did not receive postmastectomy RT were lower in the AC+T arm, the difference was not statistically significant. Despite the lack of protocol guidelines, RT use did not differ between arms, nor did RT dose, treatment interruption, or completion.
CONCLUSION: Despite the delay to RT during additional chemotherapy, adjuvant AC+T afforded better local control than AC alone in patients treated with breast-conserving therapy. Addition of paclitaxel did not adversely affect delivery or ability to tolerate RT, as indicated by similar rates of completion of timely, full-dose RT between arms.
INTRODUCTION
Despite the improvement of systemic disease control with additional chemotherapy, delay to adjuvant radiotherapy (RT) could adversely affect local control.2每6 However, the superior efficacy of AC+T could translate into improved local control. To determine the effect on local control of the additional four cycles of paclitaxel, we evaluated locoregional recurrence (LRR) in patients treated with AC versus AC+T. This was, in fact, one of the primary objectives of Intergroup 0148.
Intergroup 0148 required adjuvant RT after breast-conserving surgery (BCS), but adjuvant postmastectomy RT was discretionary. The use of postmastectomy RT for patients at intermediate risk of LRR is highly controversial.7每11 Although postmastectomy RT reduces the risk of LRR by two thirds, translating into improved breast cancer-specific mortality, the benefit is at least partially offset by radiation-induced toxicity.12每14 Modern RT techniques likely reduce the risk of radiation-induced cardiac sequelae, resulting in more favorable risk-to-benefit ratio.15,16 Nonetheless, the magnitude of the benefit of postmastectomy RT depends also on the risk of LRR without RT. Rates of LRR in patients treated with mastectomy and adjuvant anthracycline- or non-anthracycline-based chemotherapy without adjuvant RT are available to estimate the benefit of postmastectomy RT.17 However, if more efficacious chemotherapy regimens significantly reduce LRR, some patients who traditionally were estimated to be at intermediate risk of LRR may actually be at lower risk. Thus we wished to determine LRR rates in patients treated with AC versus AC+T who were not treated with postmastectomy RT.
Taxanes are potent radiosensitizers.18,19 Although RT was delivered after completion of chemotherapy, a potential concern is that paclitaxel may have increased RT-related toxicity or impaired ability to deliver timely, full-dose RT. Therefore, we also wished to determine whether addition of paclitaxel adversely affected RT delivery. Because Intergroup 0148 was designed to address chemotherapy-related questions, RT-related data were not prospectively collected. Thus data regarding whether patients were treated with postmastectomy RT and compliance with protocol-stipulated breast RT were unknown. To address the issues of effect of paclitaxel on LRR and RT delivery, we retrospectively collected RT treatment information for the patients enrolled onto Intergroup 0148 through CALGB-participating institutions to determine the following: LRR rates in patients treated with RT with or without paclitaxel, LRR rates in patients treated with mastectomy without postmastectomy RT with or without paclitaxel, and RT delivery in patients treated with RT with or without paclitaxel.
METHODS
Patients treated with BCS were required by protocol to receive adjuvant RT after completion of chemotherapy, but no other RT treatment guidelines were given. RT treatment ports were not protocol-specified; some patients received RT targeting both breast and regional lymph nodes, whereas others received breast RT only. The use of postmastectomy RT was neither required nor forbidden in Intergroup 0148. Rather, postmastectomy RT was elective, left to the discretion of the treating physician and patient. If delivered, postmastectomy RT was given after completion of adjuvant chemotherapy.
Toxicity Monitoring and Follow-Up
Acute toxicity was monitored during chemotherapy but was not specifically recorded during or after RT. The exception to this is cardiotoxicity; left ventricular ejection fraction was measured at baseline and at 5 years. Post-treatment evaluations included physical examination every 3 months for the first year, every 6 months for years 2 and 3 of follow-up, and yearly thereafter, in addition to annual mammogram and chest x-ray.
RT Data Retrieval
CALGB-participating institutions were contacted by staff at the Quality Assurance Review Center to determine whether enrolled patients had received RT. If patients had received RT, treatment charts were requested. Data extracted from the treatment charts by staff at the Quality Assurance Review Center included total dose, dose per fraction, number of fractions, treatment volumes, treatment dates, and whether bolus or boost was used.
Statistical Analysis
Analyses of arm differences in LRR were examined within three subgroups: mastectomy patients who received RT, mastectomy patients who did not receive RT, and patients with breast-conserving therapy who received RT. Figure 1 shows how the 3,170 patients on Intergroup 0148 are separated into the subgroups used in the analyses. Five-year incidences of LRR and their SEs were calculated with the cumulative incidence method.20 Arm differences in cumulative incidence of LRR were tested with the statistic proposed by Fine and Gray.21 LRR was defined in two distinct ways. First, time to LRR as first failure (also called isolated LRR) was defined as time from randomization to date of LRR as the first event; if distant failure or death occurred as the first event, then these events were treated as competing risks. Second, time to LRR as any component of failure was defined as time from randomization to date of LRR, regardless of whether distant failure had occurred first; that is, distant failures were ignored, and only death was treated as a competing risk. Time between chemotherapy and RT was defined as the number of days between the final dose of chemotherapy and the first day of RT. Median follow-up time for 738 patients without any (local or distant) event was 5.6 years (range, 0.8 to 7.7 years). Differences between arms on continuous variables such as total RT dose were tested with the Student's t test. Differences between arms on proportions were tested with Fisher's exact test. A two-sided P value less than .05 was considered statistically significant. Statistical analysis was performed at the CALGB Statistical Center.
RESULTS
The data collected on local recurrence did not distinguish ipsilateral breast recurrence from regional nodal recurrence; occurrence of both or either was coded as LRR. Because LRR rates could differ depending on volume of radiation, and because nodal recurrence could be less likely in patients whose regional lymph nodes were irradiated, we compared LRR between arms in the subset of 96 BCS patients treated homogeneously with breast and nodal RT. The probability of BCS patients receiving nodal RT did not differ between the AC and AC+T treatment arms (45 [47%] of 95 patients v 51 [49%] of 104 patients, respectively). An effect of paclitaxel on LRR was still seen (Figs 3A and 3B).
LRR After Postmastectomy RT With or Without Paclitaxel
Table 3 shows disease and patient characteristics by arm of patients who were treated with mastectomy. Despite the lack of protocol guidelines, use of elective postmastectomy RT did not differ between arms. Recurrence patterns for 98 AC and 87 AC+T patients treated with postmastectomy RT are shown in Table 4. The incidence of LRR in these patients was low in both the AC and AC+T treatment arms (Figs 4A and 4B). The 5-year incidence of isolated LRR for patients treated with AC was 4.3% (SE = 2.1) versus 3.5% (SE = 2.0) for patients treated with AC+T. The 5-year incidences of LRR as any component of failure were identical to these. Thus delay to postmastectomy RT while receiving additional chemotherapy did not impair efficacy of RT.
LRR With or Without Paclitaxel in Patients Who Did Not Receive Postmastectomy RT
Recurrence patterns for the 253 AC and 245 AC+T patients who did not receive elective postmastectomy RT are given in Table 5. The cumulative incidence of LRR was not significantly different between arms (Figs 5A and 4B). The 5-year incidence of isolated LRR for patients treated with AC was 10.8% (SE = 2.0) versus 8.8% (SE = 1.9) for patients treated with AC+T. The 5-year incidence of LRR as any component of failure for patients treated with AC was 14.9% (SE = 2.3) versus 11.7% (SE = 2.1) for patients treated with AC+T. Because estimates of the risk of LRR in patients treated with or without paclitaxel are particularly relevant for evaluating the risk-to-benefit ratio of controversial postmastectomy RT in patients at intermediate risk for recurrence, we evaluated rates of LRR in postmastectomy patients with one to three involved lymph nodes who did not receive RT. The cumulative incidence of isolated LRR in patients treated with AC versus AC+T was 9.3% (SE = 2.6) versus 5.2% (SE = 2.1), respectively (P = .17). As shown in Table 6, among the analogous group of patients with four or more nodes, the cumulative incidence was identical for AC as for AC+T (12.4%), although the interaction between treatment arm and number of nodes was not significant (P = .36).
Effect of Paclitaxel on RT Delivery
Taxanes are potent radiosensitizers. Thus although the sequential addition of paclitaxel improved LRR, paclitaxel could also have increased RT-related toxicity. Acute chemotherapy-related toxicity and long-term cardiac toxicity were captured on Intergroup 0148, but RT-related toxicity was not prospectively monitored. To determine whether 340 mastectomy and BCS patients tolerated RT as well after AC+T as AC, we examined whether patients completed prescribed therapy, RT treatment interruption, time required to complete RT, and total dose. There was no difference in mean total RT dose or duration, percentage of patients who completed RT, or incidence of treatment interruptions between arms (Table 7). There was also no difference in the time from completion of chemotherapy to initiation of RT, suggesting that there was no excess toxicity in the AC+T arm that consistently resulted in delay to initiation of RT after completion of chemotherapy. Thus completion of timely, full-dose RT was not adversely affected by the addition of paclitaxel, suggesting that there was no clinically significant increase in acute RT-related toxicity.
DISCUSSION
It is possible that local control could be further improved by earlier delivery of RT, as occurs with dose-dense scheduling of adjuvant chemotherapy. Analysis of CALGB 9741 may help to distinguish an effect of paclitaxel versus duration of chemotherapy and delay to RT on local control by comparing local control rates in patients who received RT after dose-dense AC+T versus conventional AC+T. Although it is possible that local control could be further improved by earlier delivery of RT, such as between the AC and paclitaxel phases, the potential improvement in local control should be balanced against the potential for decreased systemic efficacy with delay of systemic therapy.6
One of the more controversial subjects in breast cancer treatment is the use of elective postmastectomy RT. Although results of recent trials and meta-analyses indicate that postmastectomy RT likely improves survival in select patients, the magnitude of the benefit depends on the risk of LRR as the first site of recurrence.29每33 Five-year local recurrence rates in large, randomized series of mastectomy and systemic therapy range from 2% to 11% in patients treated with adjuvant RT versus 5% to 25% in patients treated without adjuvant RT.34每37 Although postmastectomy RT delivery was not controlled in this trial, our retrospective review of RT delivery provides useful information regarding LRR rates in patients treated with the addition of paclitaxel. The incidence of isolated LRR in patients treated with mastectomy without adjuvant RT in our trial was 11% at 5 years for those treated with AC and 9% for those treated with AC+T. The risk of LRR was much less (approximately 4%) in those treated with adjuvant RT.
In the subset of patients for whom postmastectomy RT is most controversial (ie, intermediate-risk patients with one to three involved lymph nodes), we found that the risk of isolated local recurrence in patients randomly assigned to receive AC was higher than those who received AC+T after mastectomy without RT (9.3% v 5.2%, respectively). This difference was not statistically significant. Our study, with only 18 events in the relevant subset, did not have the power to detect a true difference of this magnitude. It may be possible to discern an effect of paclitaxel, if it indeed exists, on LRR in patients with one to three involved lymph nodes treated with mastectomy without adjuvant RT if our data are combined with the similarly treated cohort from National Surgical Breast and Bowel Project (NSABP) Trial B-28. It should be noted that our follow-up time is relatively short and that longer follow-up with more local events will also increase the power to see a difference. The issue of local effect of AC+T is particularly relevant, because the randomized trial designed to specifically determine the benefit of postmastectomy RT in intermediate-risk patients treated with adjuvant anthracycline-containing chemotherapeutic regimens has been prematurely terminated because of low accrual. If chemotherapeutic advances truly reduce the risk of LRR after mastectomy, then the role of postmastectomy RT may be diminished.
However, we emphasize the limitations inherent in our study. Postmastectomy RT delivery was not controlled, allowing potential for bias or imbalance between groups. The data in the postmastectomy subset should be interpreted with the caution appropriate to retrospective reviews.
One caveat in interpretation of the potential locoregional benefit of AC+T is that the risk of LRR after mastectomy in the AC arm was higher in our study than has been reported in some others. For instance, NSABP B-06 reported an LRR rate of 6% at 8 years for node-positive disease treated with breast-conserving RT and adjuvant chemotherapy.38 Although eligibility for NSABP B-06 was limited to a tumor size of 4 cm, a similar incidence of local recurrence was identified in the adjuvant arm of NSABP B-18, which allowed larger tumors.39 One explanation for the higher rates of local recurrence is that our definition of local recurrence included recurrence in the treated breast or in the regional lymph nodes, whereas the NSABP studies discussed above specifically define in-breast recurrence. Furthermore, actuarial estimates of LRR rates in different studies may be difficult to reconcile because of competing risks of failure in other sites.40 A review of failure patterns in patients treated with breast-conserving therapy at the Joint Center for Radiation Therapy demonstrated an 8-year crude local failure rate of 34% in patients with involved lymph nodes who received radiation treatment to the breast without regional nodal irradiation.41 One third of the recurrences were regional recurrences and would thus not have been indicated in NSABP's rates of ipsilateral breast recurrence. Because patients treated with breast-conserving therapy on our trial were also likely to be treated with breast-only RT, recurrence in the unirradiated regional lymph nodes may account for higher rates of LRR in this study compared with trials that report rates of recurrence only in the irradiated breast. LRR rates in patients who received elective nodal irradiation were still relatively high in the AC arm (13% at 5 years), but these patients also had a higher burden of nodal involvement and thus were likely at higher risk of LRR than many patients treated on early-stage breast-conserving therapy trials. Margin status clearly influences the risk of local recurrence; although eligibility was restricted in our study to patients whose tumors were excised with negative margins, we do not know how close the margins were.9,11,12,42
Patients treated on this trial were less likely to receive postmastectomy RT than those treated today. It is therefore encouraging to see that the delay to RT because of sequential delivery of AC+T did not adversely affect LRR. In patients who received postmastectomy RT, recurrence rates were very low, obscuring any potential effect of paclitaxel on local control in this subset. With the increased use of AC+T and postmastectomy RT, we might hope to see lower recurrence rates than previously.
We discerned no effect of the addition of paclitaxel on ability to complete timely, full-dose RT, suggesting that paclitaxel did not significantly increase acute toxicity during RT. However, it should be noted that we were unable to evaluate with confidence whether addition of paclitaxel increased RT-related toxicity, because RT-specific toxicity, acute or chronic, was not prospectively captured. Ongoing CALGB trials are prospectively evaluating acute and chronic RT-related toxicity. It is particularly important to evaluate the possibility of increased toxicity as more patients receive paclitaxel as a component of their adjuvant regimen, particularly as delivery of chemotherapy is intensified. At least two studies have reported increased rates of radiation pneumonitis with concurrent and sequential taxane-RT regimens.43,44 Although some studies indicate no significant increase in acute toxicity with concurrent taxane-RT regiments, the fact that sequential addition of paclitaxel demonstrated no adverse effect on RT efficacy may temper enthusiasm for concurrent therapy in all but high-risk patients.45,46
Appendix
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Supported by grant Nos. CA47559, CA33601, CA29511, CA03927, CA21060, CA60138, and CA77651. The research for Cancer and Leukemia Group B 9344 was supported in part by grants from the National Cancer Institute (grant No. CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, Chair) and grant No. CA29511 to the Quality Assurance Review Center (T.J. FitzGerald, MD, Director).
The contents of the manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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17. Recht A, Gray R, Davidson NE, et al: Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: Experience of the Eastern Cooperative Oncology Group. J Clin Oncol 17:1689每1700, 1999
18. Milas L, Milas MM, Mason KA: Combination of taxanes with radiation: Preclinical studies. Semin Radiat Oncol 9:12每26, 1999
19. Choy H: Concurrent paclitaxel and radiation therapy in the treatment of solid tumors. Semin Radiat Oncol 9:1每3, 1999
20. Kalbfleisch J, Prentice R: The statistical analysis of failure time data. New York, NY, John Wiley and Sons, 1980
21. Fine J, Gray R: A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94:496每509
22. Fisher B, Dignam J, Mamounas EP, et al: Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: Eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol 14:1982每1992, 1996
23. Park CC, Mitsumori M, Nixon A, et al: Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breast cancer: Influence of margin status and systemic therapy on local recurrence. J Clin Oncol 18:1668每1675, 2000
24. Buchholz TA, Tucker SL, Erwin J, et al: Impact of systemic treatment on local control for patients with lymph node-negative breast cancer treated with breast-conservation therapy. J Clin Oncol 19:2240每2246, 2001
25. Fisher B, Brown AM, Dimitrov NV, et al: Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: Results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 8:1483每1496, 1990
26. Wallgren A, Bernier J, Gelber RD, et al: Timing of radiotherapy and chemotherapy following breast-conserving surgery for patients with node-positive breast cancer: International Breast Cancer Study Group. Int J Radiat Oncol Biol Phys. 35:649每659, 1996
27. Buzdar AU, Kau SW, Smith TL, et al: The order of administration of chemotherapy and radiation and its effect on the local control of operable breast cancer. Cancer 71:3680每3684, 1993
28. Leonard CE, Wood ME, Zhen B, et al: Does administration of chemotherapy before radiotherapy in breast cancer patients treated with conservative surgery negatively impact local control J Clin Oncol 13:2906每2915, 1995
29. Overgaard M, Hansen PS, Overgaard J, et al: Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy: Danish Breast Cancer Cooperative Group 82b Trial. N Engl J Med 337:949每955, 1997
30. Overgaard M, Jensen MB, Overgaard J, et al: Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet 353:1641每1648, 1999
31. Ragaz J, Jackson SM, Le N, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 337:956每962, 1997
32. Whelan TJ, Julian J, Wright J, et al: Does locoregional radiation therapy improve survival in breast cancer A meta-analysis. J Clin Oncol 18:1220每1229, 2000
33. Van de Steene J, Soete G, Storme G: Adjuvant radiotherapy for breast cancer significantly improves overall survival: The missing link. Radiother Oncol 55:263每272, 2000
34. McArdle CS, Crawford D, Dykes EH, et al: Adjuvant radiotherapy and chemotherapy in breast cancer. Br J Surg 73:264每266, 1986
35. Ahmann DL, O'Fallon JR, Scanlon PW, et al: A preliminary assessment of factors associated with recurrent disease in a surgical adjuvant clinical trial for patients with breast cancer with special emphasis on the aggressiveness of therapy. Am J Clin Oncol 5:371每381, 1982
36. Griem KL, Henderson IC, Gelman R, et al: The 5-year results of a randomized trial of adjuvant radiation therapy after chemotherapy in breast cancer patients treated with mastectomy. J Clin Oncol 5:1546每1555, 1987
37. Fowble B, Gray R, Gilchrist K, et al: Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy. J Clin Oncol 6:1107每1117, 1988
38. Fisher B, Redmond C, Poisson R, et al: Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 320:822每828, 1989
39. Fisher B, Bryant J, Wolmark N, et al: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol 16:2672每2685, 1998
40. Gelman R, Gelber R, Henderson IC, et al: Improved methodology for analyzing local and distant recurrence. J Clin Oncol 8:548每555, 1990
41. Galper S, Recht A, Silver B, et al: Factors associated with regional nodal failure in patients with early stage breast cancer with 0-3 positive axillary nodes following tangential irradiation alone. Int J Radiat Oncol Biol Phys 45:1157每1166, 1999
42. Cuzick J, Stewart H, Peto R, et al: Overview of randomized trials of postoperative adjuvant radiotherapy in breast cancer. Cancer Treat Rep 71:15每29, 1987
43. Taghian AG, Assaad SI, Niemierko A, et al: Risk of pneumonitis in breast cancer patients treated with radiation therapy and combination chemotherapy with paclitaxel. J Natl Cancer Inst 93:1806每1811, 2001
44. Hanna YM, Baglan KL, Stromberg JS, et al: Acute and subacute toxicity associated with concurrent adjuvant radiation therapy and paclitaxel in primary breast cancer therapy. Breast J 8:149每153, 2002
45. Bellon JR, Lindsley KL, Ellis GK, et al: Concurrent radiation therapy and paclitaxel or docetaxel chemotherapy in high-risk breast cancer. Int J Radiat Oncol Biol Phys 48:393每397, 2000
46. Formenti SC, Symmans WF, Volm M, et al: Concurrent paclitaxel and radiation therapy for breast cancer. Semin Radiat Oncol 9:34每42, 1999(Carolyn I. Sartor, Berced)
Cancer and Leukemia Group B Statistical Center, Durham, NC
Quality Assurance Review Center, Providence, RI
Medical University of South Carolina, Charleston, SC
State University of New York Upstate Medical University, Syracuse
Memorial Sloan-Kettering Cancer Center, New York, NY
University of California San Francisco, San Francisco, CA
ABSTRACT
METHODS: Eligible patients were randomly assigned to receive adjuvant AC versus AC+T chemotherapy. RT was required if breast-conserving surgery was performed but was elective after mastectomy. Information about RT delivery was retrospectively collected. Cumulative incidence of locoregional recurrence (LRR), use of elective RT, and RT delivery were compared between treatment arms.
RESULTS: For patients treated with breast-conserving surgery and RT, the 5-year cumulative incidence of isolated LRR was 9.7% in the AC arm and 3.7% in the AC+T arm (P = .04) and of LRR as any component of failure was 12.9% versus 6.1%, respectively (P = .04). Although LRR rates in patients who did not receive postmastectomy RT were lower in the AC+T arm, the difference was not statistically significant. Despite the lack of protocol guidelines, RT use did not differ between arms, nor did RT dose, treatment interruption, or completion.
CONCLUSION: Despite the delay to RT during additional chemotherapy, adjuvant AC+T afforded better local control than AC alone in patients treated with breast-conserving therapy. Addition of paclitaxel did not adversely affect delivery or ability to tolerate RT, as indicated by similar rates of completion of timely, full-dose RT between arms.
INTRODUCTION
Despite the improvement of systemic disease control with additional chemotherapy, delay to adjuvant radiotherapy (RT) could adversely affect local control.2每6 However, the superior efficacy of AC+T could translate into improved local control. To determine the effect on local control of the additional four cycles of paclitaxel, we evaluated locoregional recurrence (LRR) in patients treated with AC versus AC+T. This was, in fact, one of the primary objectives of Intergroup 0148.
Intergroup 0148 required adjuvant RT after breast-conserving surgery (BCS), but adjuvant postmastectomy RT was discretionary. The use of postmastectomy RT for patients at intermediate risk of LRR is highly controversial.7每11 Although postmastectomy RT reduces the risk of LRR by two thirds, translating into improved breast cancer-specific mortality, the benefit is at least partially offset by radiation-induced toxicity.12每14 Modern RT techniques likely reduce the risk of radiation-induced cardiac sequelae, resulting in more favorable risk-to-benefit ratio.15,16 Nonetheless, the magnitude of the benefit of postmastectomy RT depends also on the risk of LRR without RT. Rates of LRR in patients treated with mastectomy and adjuvant anthracycline- or non-anthracycline-based chemotherapy without adjuvant RT are available to estimate the benefit of postmastectomy RT.17 However, if more efficacious chemotherapy regimens significantly reduce LRR, some patients who traditionally were estimated to be at intermediate risk of LRR may actually be at lower risk. Thus we wished to determine LRR rates in patients treated with AC versus AC+T who were not treated with postmastectomy RT.
Taxanes are potent radiosensitizers.18,19 Although RT was delivered after completion of chemotherapy, a potential concern is that paclitaxel may have increased RT-related toxicity or impaired ability to deliver timely, full-dose RT. Therefore, we also wished to determine whether addition of paclitaxel adversely affected RT delivery. Because Intergroup 0148 was designed to address chemotherapy-related questions, RT-related data were not prospectively collected. Thus data regarding whether patients were treated with postmastectomy RT and compliance with protocol-stipulated breast RT were unknown. To address the issues of effect of paclitaxel on LRR and RT delivery, we retrospectively collected RT treatment information for the patients enrolled onto Intergroup 0148 through CALGB-participating institutions to determine the following: LRR rates in patients treated with RT with or without paclitaxel, LRR rates in patients treated with mastectomy without postmastectomy RT with or without paclitaxel, and RT delivery in patients treated with RT with or without paclitaxel.
METHODS
Patients treated with BCS were required by protocol to receive adjuvant RT after completion of chemotherapy, but no other RT treatment guidelines were given. RT treatment ports were not protocol-specified; some patients received RT targeting both breast and regional lymph nodes, whereas others received breast RT only. The use of postmastectomy RT was neither required nor forbidden in Intergroup 0148. Rather, postmastectomy RT was elective, left to the discretion of the treating physician and patient. If delivered, postmastectomy RT was given after completion of adjuvant chemotherapy.
Toxicity Monitoring and Follow-Up
Acute toxicity was monitored during chemotherapy but was not specifically recorded during or after RT. The exception to this is cardiotoxicity; left ventricular ejection fraction was measured at baseline and at 5 years. Post-treatment evaluations included physical examination every 3 months for the first year, every 6 months for years 2 and 3 of follow-up, and yearly thereafter, in addition to annual mammogram and chest x-ray.
RT Data Retrieval
CALGB-participating institutions were contacted by staff at the Quality Assurance Review Center to determine whether enrolled patients had received RT. If patients had received RT, treatment charts were requested. Data extracted from the treatment charts by staff at the Quality Assurance Review Center included total dose, dose per fraction, number of fractions, treatment volumes, treatment dates, and whether bolus or boost was used.
Statistical Analysis
Analyses of arm differences in LRR were examined within three subgroups: mastectomy patients who received RT, mastectomy patients who did not receive RT, and patients with breast-conserving therapy who received RT. Figure 1 shows how the 3,170 patients on Intergroup 0148 are separated into the subgroups used in the analyses. Five-year incidences of LRR and their SEs were calculated with the cumulative incidence method.20 Arm differences in cumulative incidence of LRR were tested with the statistic proposed by Fine and Gray.21 LRR was defined in two distinct ways. First, time to LRR as first failure (also called isolated LRR) was defined as time from randomization to date of LRR as the first event; if distant failure or death occurred as the first event, then these events were treated as competing risks. Second, time to LRR as any component of failure was defined as time from randomization to date of LRR, regardless of whether distant failure had occurred first; that is, distant failures were ignored, and only death was treated as a competing risk. Time between chemotherapy and RT was defined as the number of days between the final dose of chemotherapy and the first day of RT. Median follow-up time for 738 patients without any (local or distant) event was 5.6 years (range, 0.8 to 7.7 years). Differences between arms on continuous variables such as total RT dose were tested with the Student's t test. Differences between arms on proportions were tested with Fisher's exact test. A two-sided P value less than .05 was considered statistically significant. Statistical analysis was performed at the CALGB Statistical Center.
RESULTS
The data collected on local recurrence did not distinguish ipsilateral breast recurrence from regional nodal recurrence; occurrence of both or either was coded as LRR. Because LRR rates could differ depending on volume of radiation, and because nodal recurrence could be less likely in patients whose regional lymph nodes were irradiated, we compared LRR between arms in the subset of 96 BCS patients treated homogeneously with breast and nodal RT. The probability of BCS patients receiving nodal RT did not differ between the AC and AC+T treatment arms (45 [47%] of 95 patients v 51 [49%] of 104 patients, respectively). An effect of paclitaxel on LRR was still seen (Figs 3A and 3B).
LRR After Postmastectomy RT With or Without Paclitaxel
Table 3 shows disease and patient characteristics by arm of patients who were treated with mastectomy. Despite the lack of protocol guidelines, use of elective postmastectomy RT did not differ between arms. Recurrence patterns for 98 AC and 87 AC+T patients treated with postmastectomy RT are shown in Table 4. The incidence of LRR in these patients was low in both the AC and AC+T treatment arms (Figs 4A and 4B). The 5-year incidence of isolated LRR for patients treated with AC was 4.3% (SE = 2.1) versus 3.5% (SE = 2.0) for patients treated with AC+T. The 5-year incidences of LRR as any component of failure were identical to these. Thus delay to postmastectomy RT while receiving additional chemotherapy did not impair efficacy of RT.
LRR With or Without Paclitaxel in Patients Who Did Not Receive Postmastectomy RT
Recurrence patterns for the 253 AC and 245 AC+T patients who did not receive elective postmastectomy RT are given in Table 5. The cumulative incidence of LRR was not significantly different between arms (Figs 5A and 4B). The 5-year incidence of isolated LRR for patients treated with AC was 10.8% (SE = 2.0) versus 8.8% (SE = 1.9) for patients treated with AC+T. The 5-year incidence of LRR as any component of failure for patients treated with AC was 14.9% (SE = 2.3) versus 11.7% (SE = 2.1) for patients treated with AC+T. Because estimates of the risk of LRR in patients treated with or without paclitaxel are particularly relevant for evaluating the risk-to-benefit ratio of controversial postmastectomy RT in patients at intermediate risk for recurrence, we evaluated rates of LRR in postmastectomy patients with one to three involved lymph nodes who did not receive RT. The cumulative incidence of isolated LRR in patients treated with AC versus AC+T was 9.3% (SE = 2.6) versus 5.2% (SE = 2.1), respectively (P = .17). As shown in Table 6, among the analogous group of patients with four or more nodes, the cumulative incidence was identical for AC as for AC+T (12.4%), although the interaction between treatment arm and number of nodes was not significant (P = .36).
Effect of Paclitaxel on RT Delivery
Taxanes are potent radiosensitizers. Thus although the sequential addition of paclitaxel improved LRR, paclitaxel could also have increased RT-related toxicity. Acute chemotherapy-related toxicity and long-term cardiac toxicity were captured on Intergroup 0148, but RT-related toxicity was not prospectively monitored. To determine whether 340 mastectomy and BCS patients tolerated RT as well after AC+T as AC, we examined whether patients completed prescribed therapy, RT treatment interruption, time required to complete RT, and total dose. There was no difference in mean total RT dose or duration, percentage of patients who completed RT, or incidence of treatment interruptions between arms (Table 7). There was also no difference in the time from completion of chemotherapy to initiation of RT, suggesting that there was no excess toxicity in the AC+T arm that consistently resulted in delay to initiation of RT after completion of chemotherapy. Thus completion of timely, full-dose RT was not adversely affected by the addition of paclitaxel, suggesting that there was no clinically significant increase in acute RT-related toxicity.
DISCUSSION
It is possible that local control could be further improved by earlier delivery of RT, as occurs with dose-dense scheduling of adjuvant chemotherapy. Analysis of CALGB 9741 may help to distinguish an effect of paclitaxel versus duration of chemotherapy and delay to RT on local control by comparing local control rates in patients who received RT after dose-dense AC+T versus conventional AC+T. Although it is possible that local control could be further improved by earlier delivery of RT, such as between the AC and paclitaxel phases, the potential improvement in local control should be balanced against the potential for decreased systemic efficacy with delay of systemic therapy.6
One of the more controversial subjects in breast cancer treatment is the use of elective postmastectomy RT. Although results of recent trials and meta-analyses indicate that postmastectomy RT likely improves survival in select patients, the magnitude of the benefit depends on the risk of LRR as the first site of recurrence.29每33 Five-year local recurrence rates in large, randomized series of mastectomy and systemic therapy range from 2% to 11% in patients treated with adjuvant RT versus 5% to 25% in patients treated without adjuvant RT.34每37 Although postmastectomy RT delivery was not controlled in this trial, our retrospective review of RT delivery provides useful information regarding LRR rates in patients treated with the addition of paclitaxel. The incidence of isolated LRR in patients treated with mastectomy without adjuvant RT in our trial was 11% at 5 years for those treated with AC and 9% for those treated with AC+T. The risk of LRR was much less (approximately 4%) in those treated with adjuvant RT.
In the subset of patients for whom postmastectomy RT is most controversial (ie, intermediate-risk patients with one to three involved lymph nodes), we found that the risk of isolated local recurrence in patients randomly assigned to receive AC was higher than those who received AC+T after mastectomy without RT (9.3% v 5.2%, respectively). This difference was not statistically significant. Our study, with only 18 events in the relevant subset, did not have the power to detect a true difference of this magnitude. It may be possible to discern an effect of paclitaxel, if it indeed exists, on LRR in patients with one to three involved lymph nodes treated with mastectomy without adjuvant RT if our data are combined with the similarly treated cohort from National Surgical Breast and Bowel Project (NSABP) Trial B-28. It should be noted that our follow-up time is relatively short and that longer follow-up with more local events will also increase the power to see a difference. The issue of local effect of AC+T is particularly relevant, because the randomized trial designed to specifically determine the benefit of postmastectomy RT in intermediate-risk patients treated with adjuvant anthracycline-containing chemotherapeutic regimens has been prematurely terminated because of low accrual. If chemotherapeutic advances truly reduce the risk of LRR after mastectomy, then the role of postmastectomy RT may be diminished.
However, we emphasize the limitations inherent in our study. Postmastectomy RT delivery was not controlled, allowing potential for bias or imbalance between groups. The data in the postmastectomy subset should be interpreted with the caution appropriate to retrospective reviews.
One caveat in interpretation of the potential locoregional benefit of AC+T is that the risk of LRR after mastectomy in the AC arm was higher in our study than has been reported in some others. For instance, NSABP B-06 reported an LRR rate of 6% at 8 years for node-positive disease treated with breast-conserving RT and adjuvant chemotherapy.38 Although eligibility for NSABP B-06 was limited to a tumor size of 4 cm, a similar incidence of local recurrence was identified in the adjuvant arm of NSABP B-18, which allowed larger tumors.39 One explanation for the higher rates of local recurrence is that our definition of local recurrence included recurrence in the treated breast or in the regional lymph nodes, whereas the NSABP studies discussed above specifically define in-breast recurrence. Furthermore, actuarial estimates of LRR rates in different studies may be difficult to reconcile because of competing risks of failure in other sites.40 A review of failure patterns in patients treated with breast-conserving therapy at the Joint Center for Radiation Therapy demonstrated an 8-year crude local failure rate of 34% in patients with involved lymph nodes who received radiation treatment to the breast without regional nodal irradiation.41 One third of the recurrences were regional recurrences and would thus not have been indicated in NSABP's rates of ipsilateral breast recurrence. Because patients treated with breast-conserving therapy on our trial were also likely to be treated with breast-only RT, recurrence in the unirradiated regional lymph nodes may account for higher rates of LRR in this study compared with trials that report rates of recurrence only in the irradiated breast. LRR rates in patients who received elective nodal irradiation were still relatively high in the AC arm (13% at 5 years), but these patients also had a higher burden of nodal involvement and thus were likely at higher risk of LRR than many patients treated on early-stage breast-conserving therapy trials. Margin status clearly influences the risk of local recurrence; although eligibility was restricted in our study to patients whose tumors were excised with negative margins, we do not know how close the margins were.9,11,12,42
Patients treated on this trial were less likely to receive postmastectomy RT than those treated today. It is therefore encouraging to see that the delay to RT because of sequential delivery of AC+T did not adversely affect LRR. In patients who received postmastectomy RT, recurrence rates were very low, obscuring any potential effect of paclitaxel on local control in this subset. With the increased use of AC+T and postmastectomy RT, we might hope to see lower recurrence rates than previously.
We discerned no effect of the addition of paclitaxel on ability to complete timely, full-dose RT, suggesting that paclitaxel did not significantly increase acute toxicity during RT. However, it should be noted that we were unable to evaluate with confidence whether addition of paclitaxel increased RT-related toxicity, because RT-specific toxicity, acute or chronic, was not prospectively captured. Ongoing CALGB trials are prospectively evaluating acute and chronic RT-related toxicity. It is particularly important to evaluate the possibility of increased toxicity as more patients receive paclitaxel as a component of their adjuvant regimen, particularly as delivery of chemotherapy is intensified. At least two studies have reported increased rates of radiation pneumonitis with concurrent and sequential taxane-RT regimens.43,44 Although some studies indicate no significant increase in acute toxicity with concurrent taxane-RT regiments, the fact that sequential addition of paclitaxel demonstrated no adverse effect on RT efficacy may temper enthusiasm for concurrent therapy in all but high-risk patients.45,46
Appendix
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Supported by grant Nos. CA47559, CA33601, CA29511, CA03927, CA21060, CA60138, and CA77651. The research for Cancer and Leukemia Group B 9344 was supported in part by grants from the National Cancer Institute (grant No. CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, Chair) and grant No. CA29511 to the Quality Assurance Review Center (T.J. FitzGerald, MD, Director).
The contents of the manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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