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© 2003 American Society for Clinical Oncology Preoperative Twice-Weekly Paclitaxel With Concurrent Radiation Therapy Followed by Surgery and Postoperative Doxorubicin-Based Chemotherapy in Locally Advanced Breast Cancer: A Phase I/II Trial
From the Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, NY; Kenneth Norris Jr Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA; and Mayo Clinic, Jacksonville, FL. Address reprint requests to Silvia C. Formenti, MD, Department of Radiation Oncology, New York University School of Medicine, 566 First Ave, New York, NY 10016; email: silvia.formenti{at}med.nyu.edu.
Purpose: Preoperative chemotherapy is the conventional primary treatment in locally advanced breast cancer (LABC). We investigated the safety and efficacy of primary twice-weekly paclitaxel and concurrent radiation (RT) before modified radical mastectomy followed by adjuvant doxorubicin-based chemotherapy. Patients and Methods: Stage IIB (T3N0) to III LABC patients were eligible. Primary chemoradiation consisted of paclitaxel, 30 mg/m2 delivered intravenously for 1 hour twice weekly for a total of 8 to 10 weeks, and concurrent RT (45 Gy at 1.8 Gy/fraction). Modified radical mastectomy was performed at least 2 weeks after completion of chemoradiation or on recovery of skin toxicity. Postoperatively, patients who responded to paclitaxel and RT received four cycles of doxorubicin/paclitaxel, whereas patients who did not respond received doxorubicin/cytoxan. Results: Forty-four patients were accrued. Toxicity from paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). Postsurgery complications occurred in six patients (14%). The only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade 3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%), arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was 91%. Thirty-four percent of patients achieved a pathologic response in the mastectomy specimen: 16% pathologic complete responses (clearance of invasive cancer in the breast and axillary contents) and 18% pathologic partial responses (< 10 residual microscopic foci of invasive breast cancer). Conclusion: Twice-weekly paclitaxel with concurrent RT is a feasible and effective primary treatment for LABC. Future studies should compare primary chemoradiation to chemotherapy in LABC.
UNTIL RECENTLY, preoperative concurrent chemoradiation was rarely investigated in locally advanced breast cancer (LABC)1–3 because most primary regimens effective in breast cancer were anthracycline-based and toxicity caused by potent radiosensitization of normal tissues discouraged their use during radiotherapy (RT).4,5 During the last 10 years, experience acquired in other tumor types has demonstrated the feasibility of combining fluoropyrimidines, platinum compounds, and more recently, taxanes with RT. These studies often demonstrated added benefit when the two modalities were given concurrently, not only in terms of better local control but often of improved survival.6–9 We elected to study chemoradiation as a preoperative clinical paradigm that allows for pretreatment tumor biopsies to study molecular markers that are potentially associated with the histopathologic response to a specific combination therapy, similar to what has been done in gastrointestinal malignancies.10 An advantage of applying this approach to LABC is that it allows better evaluation of tumor response than conventional clinical measurements because the mastectomy specimen can be analyzed to reliably quantify residual tumor deposits. We originally piloted this approach by combining continuous infusion fluorouracil (FU) and RT in LABC.1 This study demonstrated a high pathologic response rate (34%) and revealed that tumors with mutated p53 were far less likely to respond to FU/RT. Therefore, we decided to investigate chemoradiation with paclitaxel because there is laboratory and clinical evidence that response to this drug is independent of p53 status.11–14 In addition, a prospective randomized trial in LABC showed clinical and pathologic response rates after paclitaxel equivalent to those of conventional fluorouracil/doxorubicin/cyclophosphamide polychemotherapy.15 Therefore, we chose to investigate the combination of concurrent paclitaxel and RT. The choice of twice-weekly scheduling was based on the following several lines of evidence: (1) we had originally chosen a paclitaxel dose of 60 mg/m2 weekly, but the first two patients developed remarkable skin and esophageal toxicity3; (2) experience with the twice-weekly schedule is available in non–small-cell lung cancer16; and (3) our group had generated preliminary data from sequential fine needle aspirations of LABC on the kinetics of paclitaxel-induced apoptosis and G2/M arrest supporting the twice-weekly schedule.17 We studied the safety and efficacy of primary twice-weekly paclitaxel and concurrent RT, followed by four cycles of postoperative chemotherapy with doxorubicin and paclitaxel (AT) for patients who had clinical response to the preoperative regimen; doxorubicin and cyclophosphamide (AC) were used for nonresponders. This phase I/II trial was open at three participating institutions (University of Southern California, Los Angeles, CA; New York University, New York, NY; and the Mayo Clinic, Jacksonville, FL) supported by a grant from the California Breast Cancer Research Program.
Stage IIB (limited to T3N0), IIIA, and IIIB biopsy-proven LABC patients with measurable disease and an Eastern Cooperative Oncology Group performance score of 0 to 1 were eligible for the protocol. Figure 1  outlines the study design. Initial staging consisted of blood counts with differential and platelet count, blood chemistry analysis, chest x-ray, bilateral mammography, and computed tomographic scans of chest, abdomen, and pelvis. Clinical measurements of the breast cancer and palpable axillary nodes were performed; the two largest perpendicular tumor diameters on the frontal plane were identified and their extent was documented on the patient’s skin by small black permanent tattoo dots. This procedure was performed to enable the surgeon to identify the area previously affected by the tumor in patients who achieved significant clinical resolution of the original mass after primary treatment. Three through-cut core biopsies were obtained from the primary tumor; one specimen was stored in formalin for paraffin embedding, whereas the other two were snap frozen in liquid nitrogen for molecular biology studies. Each patient was evaluated and followed at the multidisciplinary breast cancer clinic at one of the three participating institutions. All patients signed informed consent to participate in the study in accordance with guidelines of the institutional review board of each local institution.
Primary therapy consisted of weekly paclitaxel during external-beam RT. After the first two patients treated with weekly paclitaxel at 60 mg/m2 developed grade 3 skin toxicity,3 the dose of paclitaxel was modified to be delivered twice a week at 30 mg/m2 for 8 weeks. Furthermore, the protocol was modified to delay surgery to allow for recovery of skin toxicity of chemoradiation while patients were maintained on twice-weekly paclitaxel. All the patients were premedicated with dexamethasone 10 mg intravenously (IV), diphenhydramine 25 mg IV, and cimetidine 300 mg IV 30 minutes before infusion of paclitaxel. Paclitaxel was administered as a 1-hour IV infusion. RT was initiated within 1 week from the first paclitaxel dose at 1.8 to 2 Gy per fraction for a total of 25 fractions (45 to 46 Gy) to the breast, axilla, and supraclavicular nodes. No deliberate attempt was made to encompass internal mammary nodes within the treated volume. At treatment planning, the maximum dose inhomogeneity was limited to less than 5% measured by an isodose area more than 2 cm2 by using compensating blocking or wedge filters. No more than 3 cm (demagnified) of lung were allowed within the tangential fields as measured along the transverse plane of the central axis. No skin bolus was used. For left-sided primary tumors, care was taken to exclude as much of the heart as possible from the tangential fields. All fields were treated daily. Patients were evaluated weekly to monitor toxicity according to the common toxicity criteria. Clinical responses to primary chemoradiation therapy were classified by the following criteria: complete response (CR), complete disappearance of all known tumor masses; partial response (PR), a 50% or greater reduction in the product of the perpendicular measures of tumor mass; stable disease (SD), less than 50% decrease or less than 25% increase in the product of the perpendicular measures of tumor masses; and progressive disease (PD), greater than 25% increase in the product of the perpendicular measures of tumor masses. Mastectomy was performed at least 2 weeks from the last day of RT or 2 weeks after skin recovery of acute RT toxicity. Patients with skin toxicity that required a delay in mastectomy continued to receive paclitaxel until 2 weeks before scheduled surgery. Pathologic CR (pCR) was defined as the clearance of invasive cancer in the breast and axillary contents; pathologic PR (pPR) was defined as the persistence of less than 10 microscopic foci of invasive tumor cells in the breast or in the axillary contents; and lack of pathologic response (PNR) included any larger amount of residual tumor in the resected specimen. Persistence of ductal carcinoma-in-situ did not modify the classification for invasive disease described above. After surgery, patients who achieved a clinical response (CR and PR) with paclitaxel and RT received doxorubicin 60 mg/m2 and paclitaxel 200 mg/m2 (AT) every 3 weeks for four cycles; whereas those with SD or PD received doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 (AC) every 3 weeks for four cycles. Patients whose tumors were hormone receptor-positive were prescribed tamoxifen 20 mg/d for 5 years. Laboratory studies were scheduled at the time of core biopsy of primary tumor and at the time of mastectomy to investigate possible molecular variables correlated with pathologic response to preoperative paclitaxel and RT. Results of these studies are reported elsewhere.18
Statistical Considerations Pathologic and clinical CR rates were calculated using the denominator of 44. The concordance between the clinical and pathologic response rates was measured using the kappa statistic.19 Fisher’s exact test was used to evaluate the association between response and categorical variables; the P values reported are two-sided.
Between March 1997 and May 2000, 44 patients were registered onto this trial and were evaluable for toxicity assessment: 39 from the University of Southern California (89%), three from New York University (7%), and two from the Mayo Clinic (4%). Table 1 describes patient baseline characteristics. The median age was 48 years (range, 30 to 74 years). Twenty-seven women were Hispanic (61%), eight were Asian (18%), five were white (11%), and four were African-American (9%). The affected breast was the right one in 24 patients (55%) and the left one in 20 patients (45%). Seventy percent of the patients presented with T3 clinical stage and 30% presented with T4; clinical nodal stage was N0 in 46% of patients, N1 in 43%, N2 in 9%, and N3 in 2%. Sixteen patients had stage IIB (T3N0) tumors (36%), 13 had stage IIIA (30%), and 15 had stage IIIB (34%). The median follow-up time after surgery is 32 months (range, 15 to 52 months).
All 44 patients completed preoperative chemoradiation. As already mentioned, the initial paclitaxel schedule of 60 mg/m2 weekly was modified to 30 mg/m2 twice weekly because of grade 3 skin desquamation and in the first two patients. Moreover, the protocol was modified to allow time before mastectomy to recover from acute skin toxicity induced by paclitaxel and RT. Consequently, the total dose of paclitaxel varied because, as per protocol, patients continued to receive twice-weekly paclitaxel until 2 weeks before surgery. Ninety percent (40 of 44 patients) of the patients were able to receive concurrent twice-weekly paclitaxel and RT as prescribed. Four patients received a total dose of preoperative paclitaxel less than 480 mg/m2. One of the two initial patients treated at 60 mg/m2 and another treated with the 30 mg/m2 twice-weekly schedule developed grade 3 skin desquamation during chemoradiation that required interruption of chemotherapy; they received a total preoperative paclitaxel dose of 300 and 315 mg/m2, respectively. Two other patients received 330 and 390 mg/m2 because of grade 3 stomatitis and skin desquamation, and grade 2 esophagitis, respectively.
Table 2
Forty-one patients (93%) had modified radical mastectomy, and two (5%) refused mastectomy and underwent lumpectomy. One patient refused any surgery and exited the protocol. At pathologic evaluation, surgical margins were positive only in one patient; in this case, it was impossible to obtain a complete macroscopic excision of the tumor at the time of surgery because of deep infiltration of the tumor into the thoracic wall. Lymphovascular invasion was present in nine patients (21%).
Twenty-seven (63%) of the 43 patients undergoing surgery had metastatic involvement of the removed lymph nodes. Sixteen patients (37%) had three or more lymph nodes positive for cancer (range, three to 32 nodes), seven patients (16%) had one lymph node involved by cancer, and four patients (9%) had two lymph nodes involved. Ductal carcinoma-in-situ was present in seven patients (16%). Fifteen (34%) of the 44 patients achieved a pathologic response in the breast and axillary specimen; seven (16%) achieved a pCR, whereas eight (18%) achieved a pPR. The remaining 28 patients (64%) did not achieve a pathologic response according to the protocol criteria. Table 3
No association between the total preoperative paclitaxel dose (as a consequence of delayed surgery) and pathological response was found; the data are plotted in Fig 3 . For example, of the nine patients who received a cumulative paclitaxel dose of more than 480 mg/m2, four (44%) experienced a pCR or pPR compared with the 11 (31%) of 35 patients who received 480 mg/m2 or less and had a pathologic response (P = .46, Fisher’s exact test). Similarly, three (43%) of the seven patients who had an interval of more than 2 months between end of chemoradiation and surgery had a pathologic response compared with 12 (32%) of 37 who waited less than 2 months (P = .59, Fisher’s exact test).
Postmastectomy complications occurred in six patients (14%). These complications included four infections with delayed wound healing, one tram flap necrosis that required revision, and one mastitis with grade 3 dermal injury.
Forty-one of the 44 patients were available for postoperative chemotherapy analysis because one patient refused surgery (after clinical PR) and elected to exit the protocol, one developed metastasis during the immediate postoperative time and exited the protocol, and one refused further treatment. A summary of the toxicities encountered during postoperative chemotherapy is given in Table 2
Twenty-eight patients (68%) did not require any dose change. In eight patients (20%), paclitaxel dose was reduced—in three patients for grade 3 neuropathy, in three patients for grade 3 neutropenia, in one patient for grade 3 stomatitis, and in one patient for grade 3 esophagitis and Escherichia coli sepsis requiring hospitalization. Two patients (5%) had both doxorubicin and paclitaxel dose reductions—in one patient for grade 2 infection and grade 3 stomatitis, and in one patient for grade 4 leukopenia with neutropenic fever and cellulitis of the left hand.
Table 2 With a median follow-up of thirty-two months after surgery (range, 15 to 52 months), the overall estimated probability of survival is 93.9% (SE, ± 4.17%), disease-specific overall survival is 97.1% (SE, ± 2.9%), and disease-free survival is 75.6% (SE, ± 8.3%).
Primary chemoradiation followed by surgery and postoperative doxorubicin-based chemotherapy was well tolerated. Chemoradiation toxicity was mainly dermatitis within the RT field, similar to what was reported by Bellon et al.2 Several important differences, however, exist between their retrospective series and the current prospective study. First, they tested taxane-based chemoradiation postoperatively. Moreover, their total dose (50 to 54 Gy compared with 45 Gy in the current study) and technique of RT (use of bolus in 60% of patients) may explain the fact that in 38% of patients, breaks were required during the course of RT therapy, with a median duration of 8 days. Interestingly, this occurred despite their less dose-dense use of taxanes (only two patients had a weekly schedule and none had twice-weekly schedule). Especially in the preoperative setting, when the tumor is in place, it is probably counterproductive to accept treatment breaks as a trade-off for better total dose and skin dose.20 Although it was possible for all women in our study to undergo 5 weeks of uninterrupted chemoradiation, all but three patients required more than the 2 weeks planned in the protocol to recover from skin toxicity before they could undergo surgery (median time between end of RT and surgery was 4.4 weeks). In six of 44 patients, the gap from beginning of chemoradiation to surgery was longer than 3 months. After the first four patients, we amended the protocol to continue paclitaxel alone during skin recovery. When analyzed, neither the time to surgery nor the total dose of preoperative paclitaxel was strongly associated with the incidence of pathologic response to treatment. Despite cautious delaying of surgery until skin recovery was achieved, a significant rate of surgical complications was detected, suggesting persistent normal tissue morbidity from paclitaxel-based chemoradiation.21 It is reassuring to note that tolerance to postoperative AT or AC was very good; grade 4 leukopenia was observed in 10% of patients, and no other grade 4 toxicity was observed. It is interesting that no RT pneumonitis occurred among the patients accrued to this study. The finding is consistent with the University of Washington’s experience and is in contrast with that reported by Taghian et al,22 who observed RT pneumonitis in 19% of 21 breast cancer patients treated by concurrent paclitaxel and RT and 20% of 16 patients who received RT after paclitaxel. Both groups of patients, however, were treated postoperatively and after doxorubicin-based chemotherapy.22 It is possible that the sequencing of anthracycline-based chemotherapy and taxanes affects the pulmonary morbidity of subsequent RT therapy. The combination of primary or neoadjuvant chemotherapy followed by surgery and adjuvant RT is considered the standard approach to LABC,15,23–27 with 5-year disease-free and overall survival rates from contemporary trials ranging from 36% to 52% and 49% to 69%, respectively.1,25–33 High-dose regimens with autologous stem cells or bone marrow transplantation regimens have failed to significantly improve these rates.28,29
Several groups of investigators have observed a significant association between the extent of pathologic response measured in the surgical specimen with the long-term outcome of the patients. The possibility that pathologic response to primary treatment represents a reliable surrogate for disease-free and overall survival is of particular interest in a disease such as breast cancer, where even patients with stage III tumors may have a durable dormancy of their disease. Karrison et al34 analyzed a large database of breast cancer patients from the University of Chicago; stage III patients had a 28% chance per year of recurrence or death during the first 2 years after mastectomy, declining to 4% per year after 10 years, and remaining around 4% for the second decade. Table 4
With the limitation of the small number of patients, both the first chemoradiation trial of concurrent FU and RT and this study had high pathologic response rates with very limited toxicity. The pathologic response rate observed in this study is similar to that reported by Zambetti et al,35 who achieved pathologic response in 30% of 57 LABC patients treated by protracted sequential primary chemotherapy, a preoperative approach that lasted approximately 6 months. The regimen consisted of the following: (1) doxorubicin (60 mg/m2) and paclitaxel (200 mg/m2, over 3 hours) every 3 weeks for four cycles; (2) FU (700 mg/m2, days 1 to 5) and vinorelbine (20 mg/m2 day 1 and 6) every 3 weeks for three cycles; and (3) cyclophosphamide (300 mg/m2 6-hour infusion on day 1) associated with granulocyte colony-stimulating factor every 2 weeks for three cycles.35 A reasonable concern is whether pathologic responses achieved by primary chemotherapy regimens are biologically similar to those achieved by concurrent chemoradiation. Although only prospective randomized trials comparing different treatment sequencing in this disease can address this question, it is reassuring to notice that after a minimum follow-up of 5 years, 72% of the 38 LABC patients treated in our previous trial1 of primary concurrent FU and RT are alive. Moreover, patients achieving a pathologic response to the regimen have a better disease-free survival.36 An important feature of this study is its translational research component. Tumor biopsies from each patient were obtained to explore molecular correlates of pathologic response. As reported elsewhere, low human epidermal growth factor 2 (HER2)/neu and estrogen-receptor gene expression measured by reverse transcriptase polymerase chain reaction were significantly associated with pathologic response.18 Conversely, in the original study of concurrent FU and RT, p53 status at immunohistochemistry was the only significant predictor of pathologic response. The fact that tumors with different molecular characteristics are more likely to respond to the tested regimens supports the possibility that individualizing treatment on the basis of tumor characteristics might reflect on higher pathologic response rates and possibly affect time to progression and overall survival in this still challenging disease.
Supported by California Breast Cancer Research Program grant no. 4EB6000, grant no. P30 CA 14089 from the National Cancer Institute, Bethesda, MD, and grant no. M01RR00096 from the National Institutes of Health General Clinical Research Center (NCRR), Bethesda, MD, and by a research grant from Bristol-Meyer Squibb, Princeton, NJ.
1. Formenti SC, Dunnington G, Uzieli B, et al: Original p53 status predicts for pathological response in locally advanced breast cancer patients treated preoperatively with continuous infusion 5-fluorouracil and radiation therapy. Int J Radiat Oncol Biol Phys 39:1059–1068, 1997[CrossRef][Medline] 2. 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 48:393–397, 2000[CrossRef][Medline] 3. Formenti SC, Symmans WF, Volm M, et al: Concurrent paclitaxel and radiation therapy for breast cancer. Semin Radiat Oncol 9:34–42, 1999[Medline] 4. Lingos TI, Recht A, Vicini F, et al: Radiation pneumonitis in breast cancer patients treated with conservative surgery and radiation therapy. Int J Radiat Oncol Biol Phys 21:355–360, 1991[Medline]
5. Zambetti M, Moliterni A, Materazzo C, et al: Long-term cardiac sequelae in operable breast cancer patients given adjuvant chemotherapy with or without doxorubicin and breast irradiation. J Clin Oncol 19:37–43, 2001
6. Al-Sarraf M, LeBlanc M, Giri PG, et al: Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: Phase III randomized Intergroup study 0099. J Clin Oncol 16:1310–1317, 1998 7. National Cancer Institute: Concurrent chemo-radiation for cervical cancer. Clinical Announcement, Washington DC, February 22, 1999
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
