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Clinical Trials |
Breast Cancer Medicine Service, Division of Solid Tumor Oncology, Department of Medicine [M. N. F., A. D. S., M. T., M. E. M., V. C., M. M., N. S., T. G., G. D., R. S., L. N., C. H.] and Department of Epidemiology and Biostatistics [K. S. P.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021, and Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021 [M. N. F., A. D. S., M. T., M. E. M., V. C., M. M., N. S., T. G., G. D., R. S., L. N., C. H.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: Forty-two patients with resected breast carcinoma involving one or more ipsilateral axillary lymph nodes, were randomized to receive two different schedules of adjuvant chemotherapy using 14-day dosing intervals: either (a) three cycles of doxorubicin 80 mg/m2 as i.v. bolus followed sequentially by three cycles of paclitaxel 200 mg/m2 as a 24-h infusion and then by three cycles of cyclophosphamide 3.0 g/m2 as a 1-h infusion (arm A); or (b) the same schedule of doxorubicin followed by three cycles of concurrent cyclophosphamide and paclitaxel at the same doses (arm B). All cycles were supported by granulocyte colony-stimulating factor administration.
Results: Forty-one patients were assessable for toxicity and feasibility; 37 (90%) completed all planned chemotherapy. There was no treatment-related mortality; however, increased toxicity was observed on arm B compared with arm A, manifested by an increase in hospitalization for toxicity, mainly neutropenic fever, and an increased incidence of transfusion of packed RBCs transfusions for anemia. The mean delivered dose intensities for paclitaxel and cyclophosphamide were significantly greater for arm A compared with arm B (P = .01 and P = .05, respectively). There is no long-term, treatment-related toxicity, and no cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed.
Conclusions: Dose-dense sequential single-agent chemotherapy is more feasible than doxorubicin with subsequent concurrent paclitaxel and cyclophosphamide.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The Norton-Simon extension of the Skipper-Schabel model predicts that tumor cell kill will be maximized by the administration of non-cross-resistant drugs in sequence rather than in an alternating fashion (4) . The sequential schedule increases the intensity of drug exposure and is predicted to minimize tumor cell regrowth between cycles. The increased dose-exposure is a consequence of shortened intertreatment intervals for each drug or combination and not of increased doses, and such treatment is therefore called more "dose-dense" (5) . A randomized trial of doxorubicin and CMF from the National Cancer Institute of Milan can be interpreted as a "proof of principle" of the dose-dense hypothesis (6) . Here, adjuvant sequential chemotherapy with doxorubicin for four cycles followed by CMF was compared with the same regimen delivered in an alternating fashion. The sequential (more dose-dense) plan was associated with significantly improved DFS and OS. The authors concluded that, whereas in the alternating plan the four cycles of doxorubicin were spread over 27 weeks, in the sequential plan they were administered within 9 weeks, and therefore the increased dose intensity of doxorubicin could account for the superiority of the latter plan. Functionally, the intensity of the treatment was increased by shortening the intervals without increasing the dose levels of doxorubicin, providing clinical support for the exploration of the hypothesis that more dose-dense chemotherapy can improve the outcome.
On the basis of the demonstrated feasibility and promising efficacy of dose-dense doxorubicin and cyclophosphamide (AC; Refs. 7 , 8 ), and motivated by the established efficacy of paclitaxel in metastatic breast carcinoma (9) , we tested sequential doxorubicin, cyclophosphamide and paclitaxel as adjuvant therapy for patients with node-positive breast carcinoma. This pilot study demonstrated feasibility and promising early results (10) . On the basis of the evidence that concurrent paclitaxel and cyclophosphamide was feasible at full doses in patients with ovarian cancer (11) , we hypothesized that doxorubicin followed by this combination would be feasible and have the advantage of providing a shorter treatment plan and fewer total cycles of treatment. Hence, we conducted a randomized Phase II study to directly compare two dose-intensive regimens, using doxorubicin (A), cyclophosphamide (C), and paclitaxel (T) in the adjuvant setting for women with breast cancer and involved axillary lymph nodes. The objective of this trial was to: (a) determine primarily the comparative toxicity, feasibility, and delivered dose intensities of two adjuvant dose-dense treatment plans; and (b) evaluate DFS and OS of patients treated on two dose-intensive chemotherapy regimens.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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18 years of age with a Karnofsky performance status of 80% or higher, an ANC of at least 1,500/µl, a platelet count of at least 100,000/µl, a hemoglobin level of at least 10 g/dl, and normal liver, renal, and cardiac function were eligible if <8 weeks had elapsed after the final and definitive breast surgical procedure, revealing at least one ipsilateral lymph node with metastatic adenocarcinoma of the breast. Adequate cardiac function, measured as a left ventricular ejection fraction on radionuclide scan or echocardiogram, a negative baseline bone scan, and a negative chest radiograph were also required. No prior systemic therapy or radiation therapy for cancer was permitted. The protocol was approved by the institutional review board of the Memorial Sloan-Kettering Cancer Center (New York, NY), and all patients provided written informed consent.
Treatment Plan
Eligible patients were randomly assigned to either arm A or B. For both, initial treatment was the same, consisting of doxorubicin 80 mg/m2 given by i.v. bolus every 14 days for 3 cycles supported by G-CSF, (Neupogen, Amgen, Thousand Oaks, CA). The planned cumulative dose of doxorubicin was therefore 240 mg/m2. Two weeks after the third dose of doxorubicin, and when the ANC was >1,000/µl and the platelet count was 50,000/µl, patients received treatment with either (arm A) three cycles of paclitaxel 200mg/m2 given as 24-h infusion (Taxol; Bristol-Myers Squibb, Princeton, NJ) every 14 days (planned cumulative dose, 600 mg/m2), and then after the third dose, when the ANC was >1,000/µl and the platelet count was 50,000/µl, high-dose cyclophosphamide 3.0 g/m2 as a 1-h infusion for 3 courses every 14 days (planned cumulative dose, 9,000 mg/m2). All cycles again were supported by G-CSF. Arm B consisted instead of three cycles of concurrent high-dose cyclophosphamide 3.0 g/m2 and paclitaxel 200mg/m2, given at 14 days intervals and supported by G-CSF. Always, G-CSF was administered s.c. at 5 µg/kg daily on days 3–10 (8 days total) of each cycle. Actual body weight was used for body surface area (m2) calculations, but patients who were >40% above their ideal weight were dosed using the corrected weight (actual weight plus the ideal weight divided by 2). A complete blood count with leukocyte differential was performed before each cycle of chemotherapy. Total bilirubin, serum glutamicoxaloacetic transaminase, and alkaline phosphatase were obtained after the third cycle of doxorubicin and again after the third cycle of paclitaxel or paclitaxel plus cyclophosphamide.
Dose Modifications
All toxicities were graded by the National Cancer Institute’s common toxicity criteria (12)
.
Doxorubicin.
Treatment was delayed if, on the scheduled day of administration, the ANC was <1,000/µl or the platelet count was <50,000/µl. Doxorubicin was withheld for grade 2 or 3 mucositis, dysphagia, and diarrhea, but it was resumed at full dose when these toxicities resolved. The dose of doxorubicin was not reduced unless the patient developed neutropenic fever (temperature >38°C with ANC <1,000/µl) or a documented bacteremia, in which cases the subsequent doses of doxorubicin were reduced by 25%.
Paclitaxel.
Treatment was delayed if, on the scheduled day of administration, the ANC was <1,000/µl or the platelet count was <50,000/µl. The dose of paclitaxel was reduced of 20% (to 160 mg/m2) in cases of grade 3 or greater neurotoxicity, neutropenic fever (temperature >38°C with ANC, <1,000/µl), or any other grade 3 toxicity attributable to a prior dose of paclitaxel. An additional dose reduction of paclitaxel to 130 mg/m2 was allowed for recurrent grade 3 toxicity.
Cyclophosphamide.
Treatment was delayed if, on the scheduled day of administration, the ANC was <1,000/µl or the platelet count was <50,000/µl. In this case, the dose was held until the counts recovered to permissible levels but was then repeated at 100%. The dose of cyclophosphamide was reduced 20% to 2.4 g/m2 for grade 3 nonhematological toxicity. The use of 2-mercaptoethanesulfonic acid was permitted at the discretion of the treating physician, but it was not required.
Radiotherapy
After mastectomy, patients with 10 involved axillary lymph nodes and patients whose tumor exceeded 5 cm in greatest diameter received chest-wall radiotherapy. Patients treated with breast conservation also underwent radiation therapy. Treatment was 
4 weeks after the last dose of cyclophosphamide.
Tamoxifen
All patients who were amenorrheic at the end of the chemotherapy and whose tumor expressed either (or both) the estrogen or progesterone receptor were placed on a 5-year course of tamoxifen 20 mg/day, beginning 4 weeks after the last dose of cyclophosphamide or of cyclophosphamide and paclitaxel.
Follow-Up
To monitor long-term toxicities, posttreatment patients underwent a history and physical examinations every 4 months for a period of 3 years, and then every 6 months thereafter, along with complete blood count, serum glutamicoxaloacetic transaminase, alkaline phosphatase, total bilirubin, and carcinoembryonic antigen and cancer antigen 15.3 tests. Where applicable, patients received yearly mammograms. Recurrent disease was evaluated as clinically indicated and confirmed by biopsy whenever practical.
Biostatistics
The initial design of the study planned to accrue 45 patients/each arm. The primary end points were dose intensity and toxicity. Dose intensity was defined as a ratio of delivered dose [milligrams/m2 (of body surface area)]:time (weeks). Dose intensity for each drug was evaluated as the actual dose administered over the weeks during which delivery of each specific drug was planned. The trial was designed to detect a doubling of the dose-intensity of cyclophosphamide or paclitaxel in arm B as compared with arm A. Also, a comparison between the two treatment arms (A and B) of the percentage of patients who completed therapy, who were transfused with PRBC, and who were hospitalized was performed by Fisher’s exact test.
Survival curves (OS and DFS) were estimated by the method of Kaplan-Meier (13) . OS is defined as the time from the start of treatment to death. DFS is defined as the time from the start of treatment to any distant relapse. OS and DFS are reported as intent-to-treat, whereas dose intensity and toxicity are reported as per treatment actually received.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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After 21 patients were randomized to arm B of the protocol, increased toxicity was suspected in this arm, as we describe in detail below, and the protocol therefore was temporarily closed to accrual and amended on June 13, 1995, as follows. Arm B was closed and the two patients who were then on doxorubicin treatment but had not yet begun receiving concurrent paclitaxel and cyclophosphamide as per regimen B were switched instead to treatment with sequential chemotherapy as per arm A. These two patients were considered as being part of arm A for toxicity and dose-intensity analysis, but were included in the arm B group for the intent-to-treat survival analysis. Therefore, a total of 19 patients were actually treated with the concurrent schedule of arm B. No more patients were entered after May 10, 1995, and the protocol was closed to accrual on August 8, 1995.
Of the 41 patients assessable for feasibility, 37 (90%) completed all planned chemotherapy doses: 22 (100%) patients of arm A completed therapy, whereas only 15 (79%) patients of arm B completed therapy (P = 0.038). In particular, in arm B, one patient developed acute abdomen with cecal perforation after the third dose of doxorubicin and was removed from the study, and three patients withdrew consent after having been hospitalized for toxicity several times. Of these three patients, one withdrew consent after the third dose of doxorubicin, one after the first dose of concurrent paclitaxel and cyclophosphamide, and one after the second dose of concurrent paclitaxel and cyclophosphamide.
Patient Characteristics
For the 42 evaluable patients, characteristics are shown by arm of randomization in Table 1
. Patient characteristics in the two arms were balanced. Median age was similar, i.e., 45 and 47 years for arm A and arm B, respectively. The majority of patients had estrogen receptor- and/or progesterone receptor-positive disease, 81% and 86% for arm A and arm B, respectively. All these patients were prescribed hormonal treatment with tamoxifen; however, in one patient, tamoxifen was withdrawn for possible toxicity, and four patients refused it. The majority of patients underwent a modified radical mastectomy for the treatment of the primary tumor.
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. In particular, it was more severe during the concurrent treatment with paclitaxel and cyclophosphamide (arm B). Of the 19 patients treated on this arm, 8 (42%) developed grade 3 anemia, and 1 patient (5%) developed grade 4 anemia during therapy with concurrent paclitaxel and cyclophosphamide. Of the 22 patients treated on arm A, 5 (23%) developed grade 3 anemia; there was no grade 4 anemia. Also, a total of 12 patients (63%) in arm B needed to receive PRBC transfusions, whereas 8 (36%) patients needed to receive PRBC transfusions during treatment in the sequential arm of the protocol (P = 0.122; Table 3
).
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. Of the 22 patients treated with the sequential plan of paclitaxel and cyclophosphamide, 9 (41%) were hospitalized for toxicity, for a total of 14 hospitalizations (P = 0.003). With respect to patients treated on the concurrent arm of the trial, the most common reason for hospitalization was nadir fever and/or sepsis [28 episodes (76%)]; less common reasons included dehydration and diarrhea [3 episodes (8%) in 3 different patients] and mucositis [2 episodes (5%) in 2 different patients]. Other admissions were for fever without nadir (3%), and infections such as pneumonia (3%) and disseminated herpes zoster (3%). One of the patients hospitalized for dehydration secondary to diarrhea also developed supraventricular tachycardia with concomitant hypokalemia, which resolved after the appropriate medical therapy. Another patient was hospitalized at an outside institution because she developed acute abdomen with bowel perforation after the third dose of doxorubicin when she was not neutropenic. Both patients were removed from the study.
With respect to patients treated on the sequential arm of the trial, the most common reason for admission was nadir fever and/or sepsis [10 episodes (71%)].
Nonhematological
Nonhematological toxicity is shown in Table 4
. As mentioned above, a patient developed a grade 4 gastrointestinal toxicity; after the third cycle of doxorubicin, she developed a fever and acute abdomen and was found to have a perforated large bowel with fecal impaction. She was not neutropenic. She underwent an emergency colostomy, recovered fully, but was removed from the study. There were no other grade 4 nonhematological toxicities. One patient developed a grade 3 supraventricular tachycardia with concomitant hypokalemia and dehydration secondary to diarrhea after the third dose of doxorubicin; she was admitted and given the appropriate medical therapy, her cardiac rhythm was monitored via telemetry, and she was discharged later without any additional complication. This patient withdrew consent after this episode.
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Dose Reductions
Doxorubicin.
A total of 123 infusions of doxorubicin were delivered; doxorubicin was dose-reduced for toxicity only once.
Paclitaxel.
A total of 114 infusions of paclitaxel were delivered; there were 22 dose-reductions (19%), of which 16 (84%) occurred during treatment with the concurrent regimen of paclitaxel and cyclophosphamide.
Cyclophosphamide.
A total of 114 infusions of cyclophosphamide were delivered; there were no dose-reductions.
Dose Intensity
The planned dose-intensity was 40 mg/m2/week for doxorubicin, 100 mg/m2/week for paclitaxel, and 1500 mg/m2/week for cyclophosphamide. The mean delivered dose intensity for the 22 patients actually treated with the sequential schedule was 40 mg/m2/week for doxorubicin (100% of planned dose intensity), 98.2 mg/m2/week for paclitaxel (98.2% of planned dose intensity), and 1500 mg/m2/week for cyclophosphamide (100% of planned dose intensity).
The mean delivered dose intensity for the 19 patients treated with the concurrent schedule was 39.6 mg/m2/week for doxorubicin (99.4% of planned dose intensity), 76.4 mg/m2/week for paclitaxel (76.4% of planned dose intensity), and 1263.2 mg/m2/week for cyclophosphamide (84.2% of planned dose intensity; Table 5
).
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There has been no treatment-related mortality and no long-term treatment-related toxicity. Aside from the one episode of grade 3 supraventricular tachycardia, no cardiac toxicity was observed. No cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed. The median DFS and median OS have not yet been reached. At 5 years, DFS and OS of the entire population are 71.4% (95% CI, 57.7–85.1%) and 87.9% (95% CI, 78–97.9%), respectively. Because the study was closed early based on toxicity, there is insufficient power to compare overall outcomes using the two treatment plans.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The availability of hematopoietic growth factors and/or autologous hematopoietic stem cell support rendered dose escalation more feasible by limiting toxicity, thereby prompting a series of clinical experiments investigating the potential benefits of higher doses of chemotherapy. Recently, however, several randomized trials of one or two cycles of high-dose chemotherapy in the adjuvant setting have become available, and to date no overall benefit is demonstrated compared with conventional treatments (19, 20, 21, 22, 23) .
Moderate to marked dose escalation for cyclophosphamide did not prove beneficial in two NSABP trials. The NSABP B-22 and B-25 trials tested adjuvant doses of cyclophosphamide from 600 mg/m2 every 21 days x 4 doses, up to 2400 mg/m2 every 21 days x 4 doses without demonstrating an improvement in the outcomes, despite 4-fold increases in dose intensity and total dose of cyclophosphamide (24 , 25) . Disturbingly, a total of 21 cases of either acute myeloid leukemia or other myeloproliferative disorders were reported in the NSABP B-25 trial. Similar results are suggested for doxorubicin in the preliminary reports of CALGB 93-44. Here a 50% increase (60 mg/m2, 75 mg/m2, and 90 mg/m2) in doxorubicin dose and dose intensity (administered every 21 days) did not improve outcome (26) . Hence, simple dose escalation at conventional dosing intervals may be insufficient to improve outcome.
The second variable in the dose-intensity calculation, in addition to dose size, is the time duration of treatment. The Norton-Simon extension of the Skipper-Schabel model predicts that tumor cell kill will be maximized by the administration of effective drugs using the shortest possible intertreatment interval (4) . Simply stated, it suggests that a fixed fractional cell kill applied more frequently will be more effective than the same effect applied less frequently because of the impact of tumor regrowth between treatment applications. A randomized trial of doxorubicin and CMF from the National Cancer Institute of Milan (Milan, Italy) can be interpreted as a "proof of principle" for the dose-dense hypothesis: the sequential (more dose-dense) plan was, in fact, associated with significantly improved DFS and OS (6) .
On the basis of the demonstrated feasibility and promising efficacy of dose-dense doxorubicin and cyclophosphamide (AC) as demonstrated in clinical trials (7
, 8)
, and also motivated by the established efficacy of paclitaxel in metastatic breast carcinoma (9)
, we used the sequential A
C regimen as a platform to add paclitaxel as adjuvant therapy for patients with node-positive breast carcinoma (10)
. At a median follow-up exceeding 4 years, the disease-free survival for this nonrandomized trial of AC was 78%. A subsequent Phase III intergroup trial, SWOG (Southwest Oncology Group) 96-23, tested this approach (AC) compared with conventional AC with subsequent high dose chemotherapy using either cisplatin, carmustane, cyclophosphamide or cisplatin, Thiotepa, carboplatin. This trial closed February 15, 2001, but results are not available. A related trial for node-positive breast cancer patients led by CALGB (97-41) compared sequential doxorubicin, paclitaxel, and cyclophosphamide at more standard dose levels against concurrent doxorubicin/cyclophosphamide (AC), followed by paclitaxel. A separate randomization in this trial compared every-3-weeks to every-2-weeks dosing to assess the relative efficacy and toxicity of more or less dose-dense therapy.
This report of our Phase II randomized trial of sequential dose-intensive chemotherapy with doxorubicin, paclitaxel, and cyclophosphamide in patients with node-positive breast carcinoma supports the design of the trials described. We initially hypothesized that the shorter regimen (arm B) would be less toxic by virtue of its use of fewer treatment cycles. However, regimen A (sequential paclitaxel and cyclophosphamide), which had been previously demonstrated to be feasible, proved in fact to be the less difficult one, although it was still associated with a significant degree of toxicity (10) . Regimen B (concurrent paclitaxel and cyclophosphamide) was the experimental arm, on which we planned to deliver the same cumulative doses of all three agents over fewer cycles of treatment. Although previously shown feasible in ovary cancer patients, this combination had not been tested immediately after treatment with doxorubicin (11) . After 21 patients were randomized to arm B of the protocol, increased toxicity was noted clinically in this arm. A preliminary analysis showed an increase in the number of hospitalizations for toxicity, mainly neutropenic fever and sepsis (37 versus 14; P = 0.003) and an excess of hematological toxicity requiring PRBC transfusions (12 versus 8 patients; P = not significant). On the basis of this analysis, the protocol was amended, closing arm B, and accrual was stopped at 44 patients. Supporting this conclusion, all patients in the sequential arm completed the planned chemotherapy, whereas four patients in the concurrent schedule discontinued treatment because of side effects. In fact, of the 19 patients in this arm, only 15 (79%) completed all planned therapy. Interestingly, the incidence of grades 2/3 peripheral neuropathy was 36% in arm A, whereas there was none in arm B (P = 0.004); this possibly might be explained by the difference in paclitaxel delivery. There was no treatment-related mortality and no long-term treatment-related toxicity. Aside from the one episode of grade 3 supraventricular tachycardia, no cardiac toxicity was observed. No cases of acute myelogenous leukemia or myelodysplastic syndrome were observed. At 5 years, DFS and OS of the entire population are 71.4% (95% CI, 57.7–85.1%) and 87.9% (95% CI, 78–97.9%), respectively. Although regimen B proved to be significantly more toxic, regimen A was also associated with a substantial number of episodes of hospitalizations, PRBC transfusions, gastrointestinal toxicity and neuropathy. Clearly, these dose-levels can cause a high incidence of toxicity (and also higher costs), and therefore, cannot be justified for routine use in the absence of demonstrated improvement in outcome.
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FOOTNOTES |
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1 Recipient of an American Society of Clinical Oncology Career Development Award. 
2 Recipient of an American Cancer Society Career Development Award.
3 To whom requests for reprints should be addressed, at Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-6483; Fax: (212) 717-3619; E-mail: hudisc{at}mskcc.org
4 The abbreviations used are: CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; DFS, disease-free survival; OS, overall survival; ANC, absolute neutrophil count; G-CSF, granulocyte colony-stimulating factor; PRBC, packed RBCs; CI, confidence interval; CALGB, Cancer and Leukemia Group B; NSABP, National Surgical Adjuvant Breast and Bowel Project.
Received 5/22/01; revised 9/10/01; accepted 9/17/01.
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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