2002 Highlights from: 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, Florida, May 18–21, 2002

meeting

highlights

2002

Highlights From: 38th Annual Meeting of the American

Society of Clinical Oncology Orlando, Florida May 18-21, 2002 Maximal Benefit of Adjuvant Chemohormonal Therapy Achieved with Sequential Chemotherapy Followed by Tamoxifen

in postmenopausal patients with primary breast cancer. The 2 objectives of this trial were to determine whether combination chemohormonal therapy was superior to hormonal therapy alone and, if so, to determine whether the optimal administration of these agents was concurrent or sequential (tamoxifen following chemotherapy). The data from INT 0100 at an 8-year median follow-up were presented by Dr

Albain at the 38th annual meeting of the American Society of Clinical Oncology (ASCO) held in Orlando, Florida, and are summarized below.5 Patients enrolled in this trial were postmenopausal and had stage T1 or T3a, pathologic N1-N2 or clinical N0 or N1, M0 breast cancer, which was positive for estrogen receptors (ER) or progesterone receptors (PgR). Patients were randomized in a 2:3:3 ratio into 1 of 3

Anthracycline-based chemotherapy and tamoxifen hormonal therapy are widely used components of standard adjuvant systemic therapy for operable breast cancer. The com- Figure 1: Breast Intergroup Trial 0100 Treatment Schema bination of chemohormonal therapy has been shown in a Tamoxifen Alone meta-analysis1 and in a large Tamoxifen 20 mg/day p.o. x 5 years (n = 361) randomized study to reduce the risk of relapse and death2; CAF Followed by Tamoxifen however, the optimal sequencCyclophosphamide 100 mg/m2/day ing of these components has Stratify by: p.o. days 1-14 not yet been determined. Pre- • Institution Doxorubicin 30 mg/m2 days 1 and 8 clinical evidence suggests that • Cooperative group 5-Fluorouracil 500 mg/m2 tamoxifen can antagonize the R days 1 and 8 • Number of positive lymph A antitumor effects of selected every 28 days x 6 cycles nodes N D chemotherapy agents, raising (1-3 vs. ≥ 4) (n = 566) O concerns that simultaneous ad- • Hormone-receptor status M CAF/Tamoxifen I ministration of these agents (ER+/PgR– versus ER+/-/PgR+) Z Cyclophosphamide 100 mg/m2/day could lead to suboptimal outE • Interval between surgery and p.o. days 1-14 comes.3,4 randomization Doxorubicin 30 mg/m2 The North American Inter(≤ 6 weeks vs. > 6 weeks) days 1 and 8 group Trial 0100 (INT 0100) 5-Fluorouracil 500 mg/m2 was undertaken to determine days 1 and 8 every 28 days x 6 cycles the optimal sequencing of adjuvant anthracycline-containing Tamoxifen 20 mg/day p.o. x 5 years chemotherapy with tamoxifen beginning day 1 of CAF cycle 1

Tamoxifen 20 mg/day p.o. x 5 years beginning day 29 of cycle 6 of CAF

(n = 550) Medical Writer: Amy I. D’Orazio, PhD, Reviewed by: Joyce O’Shaughnessy, MD

94 • Clinical Breast Cancer June 2002

Abbreviations: CAF = cyclophosphamide/doxorubicin/5-fluorouracil; ER = estrogen receptor; PgR = progesterone receptor

Table 1: Eight-Year Estimates of Disease-Free and Overall Survival Overall Survival

Disease-Free Survival Rate (%)

Relative Improvement Compared to Tamoxifen Alone

Rate (%)

Relative Improvement Compared to Tamoxifen Alone

CAF → Tam*

67%

44%

73%

25%

CAF/Tam

62%

23%

71%

16%

Tam

55%

–

67%

–

*P = 0.004 for CAF followed by tamoxifen compared to tamoxifen alone; P = 0.03 for CAF followed by tamoxifen compared to CAF/tamoxifen Abbreviation: CAF = cyclophosphamide/doxorubicin/5-fluorouracil; Tam = tamoxifen

treatment arms. The first arm received tamoxifen alone, the second received sequential CAF (cyclophosphamide/doxorubicin/5-fluorouracil) followed by tamoxifen, and the third arm received CAF with tamoxifen (Figure 1). Tamoxifen was administered at a dose of 20 mg/day orally (p.o.) in 1 dose or in 2 divided doses in all 3 arms and was continued for 5 years. In the CAF followed by tamoxifen and the concurrent CAF/tamoxifen arms, CAF consisted of cyclophosphamide 100 mg/m2 p.o. days 1-14, doxorubicin 30 mg/m2 on days 1 and 8, and 5-fluorouracil 500 mg/m2 on days 1 and 8. Six 28-day treatment cycles of CAF were given. In the CAF followed by tamoxifen arm, tamoxifen was begun on day 29 on the sixth cycle of CAF. In the CAF/tamoxifen arm, tamoxifen was begun on day 1 of the first treatment cycle of CAF (Figure 1). Patients were stratified by institution, cooperative group, number of positive lymph nodes (1-3 vs. ≥ 4), hormone-receptor status (ER positive/PgR negative vs. ER positive or negative/PgR positive), and the interval between surgery and randomization (≤ 6 weeks vs. > 6 weeks). Fourteen hundred seventy-seven patients were enrolled. Thirty-two percent were aged ≥ 65 years, 7% had stage T3 breast cancer, and 42% had ≥ 4 positive lymph nodes. Twenty-one percent were PgR negative. The treatment arms were well balanced with regard to age, race, tumor size, type of surgery, and number of patients who had had postmastectomy chest wall radiation. Results of this trial, presented at ASCO 2001 showed both a disease-free and overall survival (OS) prolongation with combination chemohormonal therapy (sequential or concurrent) versus

tamoxifen alone.6 When the 2 combination arms were compared separately to tamoxifen alone, both the concurrent arm of CAF/tamoxifen and sequential arm of CAF followed by tamoxifen were found to prolong disease-free survival as compared to tamoxifen alone, but the relative improvement compared to tamoxifen alone was greater with the sequential arm of CAF followed by tamoxifen. The 8-year disease-free survival (DFS) rate was 67% for CAF followed by tamoxifen compared with 55% with tamoxifen alone (P = 0.004; Table 1).5 The difference in the 8-year DFS rate between sequential and concurrent therapy was statistically significant at 67% for CAF followed by tamoxifen and 62% for CAF/tamoxifen (P = 0.03). There was also a greater relative improvement in OS with the sequential arm of CAF followed by tamoxifen compared to tamoxifen alone versus the concurrent arm of CAF/tamoxifen compared to tamoxifen alone, at 25% and 16%, respectively (Table 1). The 8-year OS rates were 73% for CAF followed by tamoxifen, 71% for CAF/tamoxifen, and 67% for tamoxifen alone. The difference in the 8-year OS rates between sequential and concurrent therapy has not reached statistical significance.

Conclusion: The results of this trial with 8 years of follow-up demonstrate that sequential administration of tamoxifen following adjuvant CAF chemotherapy is preferable to concurrent administration of chemotherapy and tamoxifen. The results of Intergroup 0100 suggest some degree of antagonism of the antitumor effects of CAF and tamoxifen with concurrent administration. It is not known

whether this is due to the antiproliferative effects of tamoxifen interfering with the cytotoxicity of CAF or to decreased doxorubicin transport/metabolism with tamoxifen.3,4 Although no significant survival advantage with sequential CAF/tamoxifen has yet been seen, the investigators noted that the benefit in survival of chemohormonal therapy versus tamoxifen alone did not appear until 7 years, and the disease-free survival for sequential versus concurrent chemohormonal therapy was not observed until 8 years. ________________________________________________________________________________________________________________________________________________________

Docetaxel/Doxorubicin/ Cyclophosphamide (TAC) Produces Higher Response Rate but Similar Outcome to 5-Fluorouracil/ Doxorubicin/Cyclophosphamide (FAC) in Patients with Metastatic Breast Cancer Docetaxel and doxorubicin are 2 of the most active agents in metastatic breast cancer (MBC), and the combination of these agents produced ORRs in 57%-76% of patients and prolonged median survival times to 27.5-36 months in recent phase II trials.7-9 A large phase III trial comparing doxorubicin/ docetaxel (AT) to doxorubicin/cyclophosphamide (AC) in previously untreated MBC patients found that the ORR and 1-year progression-free survival rate were both significantly higher in the AT arm at 60% and 28%, respectively compared to 47% and 19% for AC (P = 0.012 for ORR and 0.0153 for progression-free survival).10,11 Docetaxel/doxorubicin has also been evaluated in combination with cyclophosphamide and, in a phase II trial, has proven to have a high degree of antitumor effect in MBC as well, with an ORR of 77%, a median time to progression (TTP) of 10.9 months, and median OS of 33 months.12 Based on these data, a phase III trial was undertaken to compare TAC (docetaxel/doxorubicin/cyclophosphamide) to FAC (5-fluorouracil/ doxorubicin/cyclophosphamide) as firstline therapy for patients with MBC. The mature results were recently presented

Clinical Breast Cancer June 2002 • 95

Meeting Highlights with TAC (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2) or TAC FAC (n = 242) (n = 242) FAC (5-fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, cy55% Response Rate* 44% clophosphamide 500 mg/m2) 7% Complete response 3% given every 3 weeks for 6-8 cy31.1 weeks Median Time to Progression 28.9 weeks cles. Only patients with no prior 20.6 months 22.0 months Median Overall Survival anthracycline exposure received 8 cycles of therapy. *P = 0.02 Four hundred eighty-four paAbbreviations: FAC = 5-fluorouracil/doxorubicin/cyclosphosphamide; TAC = docetaxel/doxorubicin/cyclophosphamide tients were randomized to TAC versus FAC. The 2 arms were by Dr Mackey at the 2002 ASCO meetwell balanced with regard to patient ing.13 characteristics. The median ages were 53 The objectives of this study were to years on the TAC arm and 55 years on compare the median TTP, ORR, response the FAC arm, and in both arms, the meduration, OS, toxicity, and quality of life dian KPS was 90%. Approximately 40% in patients with MBC. To be eligible for of the patients had received adjuvant the study, patients were required to meet chemotherapy, and about 10% had rethe following criteria: measurable or ceived prior anthracyclines. The populaevaluable MBC; no prior therapy for tion of patients as a whole had a fairly metastatic disease; no prior taxanes; and poor prognosis, with over 70% in each a Karnofsky performance status ≥ 60%. arm having visceral metastases and apPrior anthracycline exposure was perproximately half having 3 or more sites of mitted, provided maximum doses of 240 metastatic disease. mg/m2 of doxorubicin, 400 mg/m2 of The efficacy data are summarized in epirubicin, and 70 mg/m2 of mitoxTable 2. There was a statistically signifiantrone had not been exceeded. Eligible cant difference in response rate observed patients were randomized to treatment with TAC, at 55%, compared to 44% with FAC (P = 0.02). The proportion of complete responses (CRs) was twice Table 3: Grade 3/4 Adverse Events Seen with as high at 7% with TAC versus 3% TAC Versus FAC in Patients with MBC with FAC. However, there was no TAC FAC difference in median TTP, which (n = 238) (n = 237) was 31.1 weeks in the TAC arm and Hematologic Toxicities 28.9 weeks in the FAC arm (P = Neutropenia 81% 94% 0.51). Median OS was similar as Febrile neutropenia 5% 29% well at 20.6 months in the TAC arm and 22 months in the FAC arm. The Infection 4% 5% survival results could have been inSeptic death 3 (1%) 2 (< 1%) fluenced by the high proportion of Nonhematologic Toxicities patients on the FAC arm (39%) who received docetaxel upon disease pro< 1% Congestive heart failure 2% gression as compared to the TAC † LVEF decline ≥ 30% 3% 4%* arm, on which only 11% of patients 0 Edema 1% received further docetaxel. 3% Stomatitis 8% Grade 3/4 neutropenia and neutropenic fever were both more com6% Vomiting 5% mon in the TAC arm at 94% and 9% Nausea 8% 29% of patients, respectively, com1% Diarrhea 5% pared to 81% and only 5%, respectively, on the FAC arm. Severe in*Out of 141 evaluable patients †Out of 156 evaluable patients fection occurred with similar inciAbbreviations: FAC = 5-fluorouracil/doxorubicin/cyclophosphamide; dence in both arms, at 5% in the LVEF = left ventricular ejection fraction; MBC = metastatic breast cancer; TAC = docetaxel/doxorubicin/cyclophosphamide TAC arm and 4% in the FAC arm. Table 2: Efficacy of TAC Versus FAC in Patients with Metastatic Breast Cancer

96 • Clinical Breast Cancer June 2002

Two patients on the TAC arm and 3 on the FAC arm had a septic death. Grade 3/4 nonhematologic toxicities were uncommon. Congestive heart failure was seen in 2% of patients on the TAC arm and < 1% of patients on the FAC arm (Table 3).

Conclusion: This study shows that TAC produces a significantly higher ORR than FAC in a population of poor prognosis MBC patients. However, no advantage in TTP or survival was seen, which might be due in part, to the 39% of patients who received docetaxel following treatment with FAC compared with only 11% in the TAC arm. Patients in the TAC arm experienced more grade 3/4 neutropenia and fever, but the rates of documented infection and septic deaths were the same in both arms. The results of this trial suggest that TAC is a reasonable therapeutic option for patients who require the highest chance of achieving a therapeutic response for highly symptomatic and/or life-threatening disease. _______________________________________________________________________________________________________________________________________________________

Higher Pathologic Complete Response Rate Seen with Neoadjuvant Chemotherapy Using Weekly Versus Every-3-Week Paclitaxel Plus 5-Fluorouracil/ Doxorubicin/Cyclophosphamide Neoadjuvant therapy is emerging as a promising means of rapidly assessing the effectiveness of treatment options in patients with operable breast cancer and improving breast-conserving surgery rates. In a trial reported by the National Surgical Adjuvant Breast and Bowel Project, it was found that patients given preoperative AC (doxorubicin/cyclophosphamide) had higher rates of pathologically negative axillary lymph nodes and breast-conserving surgery compared with patients who received postoperative AC.14 One of the most compelling findings from this study was that patients who achieved a pathologic CR (pCR) with neoadjuvant AC had superior DFS and OS compared with those who had evi-

Meeting Highlights Table 4: Adverse Events Associated with Every-3-Week Versus Weekly Paclitaxel Percent of Patients

Evaluable Patients Febrile Neutropenia

Every-3-Week Paclitaxel 225 mg/m2/week

Weekly Paclitaxel 150 mg/m2/week

Weekly Paclitaxel 80 mg/m2/week

90

40

47

27%

0

0

Infection Neutropenic

5%

0

0

Non-neutropenic

11%

23%

17%

Grade 3 Neurotoxicity

15%

65%

15%

Grade 3 Myalgia/Arthralgia

38%

12%

8%

dence of residual disease at the time of surgery. Five-year DFS was 84% in the patients who achieved a pCR compared to 72% in those with residual disease. OS was also higher at 87% compared to 78%, respectively. This suggested that the achievement of a pCR is an important objective in developing new regimens for patients with operable breast cancer. Anthracycline-based chemotherapy has been the standard of care for both neoadjuvant and adjuvant treatment. Paclitaxel has been administered sequentially following adjuvant AC on the basis of its high single-agent efficacy, its unique mechanism of action, and its nonoverlapping toxicity profile with the anthracyclines.15,16 When every-3week paclitaxel was given following AC to node-positive breast cancer patients, a reduction in the relative risks of recurrence and death were observed compared with AC alone, demonstrating the effectiveness of the agent in the treatment of node-positive breast cancer.17,18 Weekly administration of paclitaxel al-

lows for higher cumulative doses to be administered than with every-3-week paclitaxel, with fewer toxic effects and a high level of antitumor activity.19 Investigators from M. D. Anderson Cancer Center conducted a randomized trial comparing every-3-week versus weekly paclitaxel followed by FAC as neoadjuvant therapy for patients with operable breast cancer. The results of this trial were presented by Dr Green at the 2002 ASCO meeting.20 This phase III trial enrolled breast cancer patients with T1-T3 N0/1 M0 operable breast cancer. Patients were randomized to preoperative treatment with paclitaxel 225 mg/m2 given as a continuous infusion over 24 hours every 3 weeks for 4 cycles or to weekly paclitaxel. The doses of weekly paclitaxel varied according to the patients’ nodal status: pathologically node-negative patients (defined by fine needle biopsy) received paclitaxel 80 mg/m2/week for 12 weeks and nodepositive patients by fine needle biopsy received paclitaxel 150 mg/m2/week for 3 of every 4 weeks for 4 treatment Table 5: Activity of Every-3-Week Versus Weekly cycles. Following paclitaxel, paPaclitaxel tients received 4 cycles of preEvery-3-Week Weekly operative FAC. Following surPaclitaxel Paclitaxel gery, patients with ER-positive (n = 127) (n = 131) and/or PgR-positive disease Response Rate 86% 86% were given tamoxifen for 5 years. Complete Response 54% 43% Two hundred fifty-eight paPartial Response 32% 43% tients with a median age of apStable Disease 7% 6% proximately 50 years were enPathologic CR* rolled. The treatment arms were well balanced with regard Node-positive patients 15% (n = 54) 29% (n = 56) to patient characteristics: over Node-negative patients 15% (n = 73) 28% (n = 75) 70% of the patients in each arm had T2-T4 disease and about *P = 0.01

45% were pathologically node positive on fine needle aspiration. The proportions of patients with hormone-receptor–positive and HER2-positive disease were evenly distributed. Adverse events are shown in Table 4. Weekly paclitaxel at a dose of 80 mg/m2/ week was the best-tolerated regimen. Every-3-week paclitaxel was associated with a 27% incidence of febrile neutropenia and a 5% incidence of neutropenic infection versus none with the weekly paclitaxel regimens. Grade 3 neurotoxicity was noted in a high proportion of patients treated with the higher dose weekly paclitaxel (65%) versus 15% of patients treated with the other 2 regimens. The clinical antitumor activity of every-3-week and weekly paclitaxel (both regimens combined) appears to be roughly the same (Table 5). The ORRs were 86% in each arm, with 54% of patients in the every-3-week paclitaxel arm and 43% of patients in the weekly paclitaxel arms, achieving a clinical CR. However, when the patients were evaluated pathologically at the time of surgery, there was a statistically significant increase (approximately double) in the proportion of pCRs in the patients treated with weekly paclitaxel compared with every-3-week paclitaxel. This difference was seen in both node-positive and node-negative patients (P = 0.01). The 2 doses of weekly paclitaxel resulted in similar pCR rates.

Conclusion: Preoperative weekly paclitaxel followed by FAC, had a significantly higher pCR rate compared to every-3-week paclitaxel followed by FAC. Paclitaxel at a dose of 80 mg/m2/week was associated with less hematologic toxicity than 225 mg/m2 every 3 weeks. Paclitaxel 80 mg/m2/week followed by FAC is a promising preoperative regimen and is recommended for further study. ________________________________________________________________________________________________________________________________________________________

Higher Response Rate but Similar Outcomes Seen with Letrozole Compared to Anastrozole in Patients with Advanced Breast Cancer Letrozole and anastrozole are non-

Clinical Breast Cancer June 2002 • 97

Meeting Highlights steroidal triazole aromatase inhibitors that are approved as first- and secondline therapies for hormone receptor–positive advanced breast cancer. An international, multicenter, randomized clinical trial comparing letrozole to anastrozole as second-line therapy for advanced breast cancer was recently undertaken. The results were presented by Dr Rose from University Hospital in Sweden at the 2002 ASCO meeting.21 The primary endpoint of this study was TTP with secondary endpoints being ORR, response and clinical benefit duration, time to treatment failure (TTF), OS, and safety. This trial enrolled postmenopausal patients with advanced breast cancer whose disease had relapsed within 12 months or progressed on adjuvant tamoxifen therapy or tamoxifen therapy for first-line treatment of metastatic disease. Demonstration of ER or PgR positivity or unknown status was also required. Patients with more than one prior chemotherapy regimen for MBC were excluded. Patients were randomized to treatment with either letrozole 2.5 mg/day p.o. or anastrozole 1 mg/day p.o.

Seven hundred thirteen patients were enrolled in this study. The 2 treatment arms were well balanced with regard to age, body-mass index, and dominant site of disease (soft tissue in 24% of patients in each arm and viscera in 52% of patients in each arm). Twentynine percent of the patients in each arm were hormone-receptor positive and slightly more than half in each arm had an unknown hormone-receptor status. Letrozole showed a superior ORR at 19% compared to 12% with anastrozole (P = 0.013; Table 6). More patients had a CR with the letrozole arm at 7% compared to 4% of patients who received anastrozole. Clinical benefit was increased as well from 23% with anastrozole to 27% with letrozole, although the difference was not statistically significant. However, for patients with bone or viscera as dominant sites of disease, the ORRs for letrozole and anastrozole were similar, with 12.9% and 11.5%, respectively, by bone and 14.1% and 9.7%, respectively, by viscera. This higher ORR did not translate into statistically significant differences in TTP, response duration, TTF, or OS.

Table 6: Efficacy of Letrozole Versus Anastrozole as Second-Line Therapy for Advanced Breast Cancer

Response Rate Complete response Clinical Benefit

Letrozole (n = 356)

Anastrozole (n = 357)

19%

12%*

7%

4%

27%

23%

*P = 0.013

There was no difference in the adverse event profiles of the 2 arms. Nausea was the most notable adverse event, seen in 8% of patients treated with letrozole and 11% of those treated with anastrozole.

Conclusion: Letrozole resulted in a higher clinical ORR than anastrozole in this study of over 700 women with advanced breast cancer who had been previously treated with tamoxifen. However, no advantage in terms of TTP or OS was seen, and both agents were well tolerated. These results support both letrozole and anastrozole as options for second-line hormonal therapy of advanced breast cancer.

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