Chiun Hsu and Chiun-Sheng Huang contributed equally to this work.
Phase II trial combining paclitaxel with 24-hour infusion cisplatin for chemotherapy-naïve patients with locally advanced or metastatic breast carcinoma
Article first published online: 31 OCT 2002
Copyright © 2002 American Cancer Society
Volume 95, Issue 10, pages 2044–2050, 15 November 2002
How to Cite
Hsu, C., Huang, C.-S., Chao, T.-Y., Lu, Y.-S., Bu, C.-F., Chen, M. M., Chang, K.-J. and Cheng, A.-L. (2002), Phase II trial combining paclitaxel with 24-hour infusion cisplatin for chemotherapy-naïve patients with locally advanced or metastatic breast carcinoma. Cancer, 95: 2044–2050. doi: 10.1002/cncr.10951
- Issue published online: 31 OCT 2002
- Article first published online: 31 OCT 2002
- Manuscript Accepted: 12 JUN 2002
- Manuscript Revised: 3 JUN 2002
- Manuscript Received: 29 MAR 2002
- National Health Research Institutes. Grant Number: NHRI-EX90-8829SP
- breast carcinoma;
- chemotherapy naïve;
Both paclitaxel and cisplatin are active as second-line chemotherapy for patients with breast carcinoma. A synergistic cytotoxicity of these two drugs has been demonstrated in vitro. This study sought to determine the efficacy of combining these two drugs in the treatment of chemotherapy-naïve patients with breast carcinoma.
The inclusion criteria for the study were 1) women with histologically proven breast carcinoma; 2) locally advanced disease, as defined by American Joint Committee on Cancer (AJCC) Stage T4 (locally advanced breast carcinoma [LABC]) or clinically proven metastases (metastatic breast carcinoma [MBC]); and 3) no prior cytotoxic chemotherapy. The regimen consisted of paclitaxel 175 mg/m2 intravenously by 3-hour infusion immediately followed by cisplatin 50 mg/m2 intravenously by 24-hour infusion on Day 1 and repeated every 3 weeks. After a maximal response to chemotherapy was achieved, patients with LABC underwent resection of their primary tumor if the procedure was not contraindicated.
From July, 1999 to January, 2001, 46 patients were enrolled into this study (28 patients with LABC and 18 patients with MBC). Their median age was 49.5 years (range, 29.8–65.5 years). A total of 205 cycles of chemotherapy were given. All patients were evaluable for toxicity, and 45 patients were evaluable for response. There were 3 complete responses (CRs) and 24 partial responses (PRs), for an overall response rate of 58.7% (95% confidence interval, 44.5–72.9%). Grade 4 hypersensitivity (asthma) to paclitaxel occurred in one patient. Grade 3–4 nausea and emesis and Grade 3–4 myelosuppression occurred in six patients and four patients, respectively. Of the 28 patients with LABC, 2 patients achieved a CR, and 14 patients achieved a PR. Twenty-seven patients underwent mastectomy patients after chemotherapy. A pathologic CR was documented in one patient. Postoperatively, 23 patients with LABC received adjuvant chemotherapy, and 18 patients with LABC received adjuvant radiotherapy. During a median follow-up of 14.6 months, 5 of 28 patients with LABC developed recurrent disease, and 2 patients died of progressive disease, whereas 3 of 18 patients with MBC died of progressive disease.
The combination of paclitaxel by 3-hour infusion and cisplatin by 24-hour infusion appears to be an active and well-tolerated regimen for chemotherapy-naïve patients with LABC or MBC. Cancer 2002;95:2044–50. © 2002 American Cancer Society.
Breast carcinoma is a major health problem for women worldwide. Although significant numbers of patients eventually die of metastatic disease, systemic chemotherapy has proven effective in prolonging survival and improving the quality of life of these patients. A continual search for new chemotherapeutic agents and regimens is mandatory.1
Paclitaxel has been one of the most extensively studied new chemotherapeutic agents in the past decade. It has substantial antitumor activity in a variety of malignancies, including ovarian, breast, and nonsmall cell lung carcinomas.2, 3 The efficacy and toxicity of paclitaxel are dose and schedule dependent. Single-agent activity of paclitaxel in patients with metastatic breast carcinoma (MBC) ranges from 20% to 50%.4–6 The most commonly used paclitaxel regimen is a 3-hour intravenous infusion at a dose of 135–200 mg/m2 every 3 weeks. The combination of paclitaxel with other antitumor drugs significantly improves its efficacy in the treatment of patients with breast carcinoma, but often at the expense of markedly enhanced toxicity. The design of paclitaxel-containing chemotherapy regimens that remain highly effective against breast carcinoma but are associated with the least possible toxicity is needed.
Cisplatin is an active agent against breast carcinoma, with a single-agent response rate of around 50% in previously untreated patients.7, 8 A synergistic cytotoxicity between paclitaxel and cisplatin has been demonstrated in preclinical and clinical studies.9, 10 It has been shown that paclitaxel plus cisplatin is a superior regimen for the treatment of patients with ovarian carcinoma and nonsmall cell lung carcinoma.11, 12 Combination treatment with paclitaxel and cisplatin has resulted in objective tumor response rates from 23% to 90% in patients with breast carcinoma.13–15 However, the incorporation of cisplatin into the treatment regimen often has enhanced the treatment-related toxicity significantly, including myelosuppression and neuropathy.
The administration of cisplatin by prolonged infusion may help alleviate the toxicity of cisplatin while maintaining its efficacy. Jacobs et al. demonstrated that a 24-hour infusion of cisplatin (average dose, 80 mg/m2 every 3 weeks) yielded a response equivalent to that of bolus injection in patients with advanced head and neck carcinoma while greatly reducing the toxicity.16 Pharmacokinetic study indicate that, with prolonged infusion of cisplatin (120 hours), the peak serum concentration was lower, and the renal and gastrointestinal side effects were reduced significantly.17 We hypothesized that, by improving the therapeutic index of cisplatin with a prolonged infusion schedule, it may be easier to combine this paclitaxel-cisplatin regimen with other treatment modalities in multidisciplinary therapy for patients with breast carcinoma. In this study, we evaluated the potential efficacy and toxicity of the regimen of paclitaxel 175 mg/m2 by 3-hour infusion followed by cisplatin 50 mg/m2 by 24-hour infusion for chemotherapy-naïve patients with breast carcinoma.
MATERIALS AND METHODS
Women with histologically diagnosed breast carcinoma who had either locally advanced breast carcinoma (LABC) or evidence of distant metastasis (MBC) were eligible for inclusion in this study if they had not received cytotoxic chemotherapy. The diagnosis of LABC was made according to the American Joint Committee on Cancer (AJCC) definition of T4 primary tumor, including one or more of the following: 1) tumor measuring > 5 cm in greatest dimension; 2) tumor involvement of the chest wall (ribs, intercostal, or serratus anterior muscles) or skin (ipsilateral cutaneous edema, ulceration, or satellite nodules); 3) clinically evident, inflammatory carcinoma; and 4) ipsilateral, fixed, axillary lymphadenopathy.18 The patients were required to have bidimensionally measurable disease on physical examination or imaging study and adequate bone marrow, liver, and kidney function, defined as white blood cells ≥ 4000/μL, absolute neutrophil count ≥ 1500/μL, platelets ≥ 100,000/μL, total bilirubin ≤ 2.0 mg/dL, transaminases ≤ 3 times the upper normal limit, serum creatinine ≤ 1.5 mg/dL, and creatinine clearance ≥ 60 mL/minute. This study was approved by the Institutional Review Boards of the participating institutions, and all patients had signed informed consent prior to enrollment into the study.
The chemotherapy regimen consisted of paclitaxel (Phyxol™; Sinphar Pharmaceutical, Taiwan) 175 mg/m2 by 3-hour intravenous infusion immediately followed by cisplatin 50 mg/m2 by 24-hour intravenous infusion on Day 1 of a 3-week cycle. The chemotherapy was administered on an outpatient basis. For safety and convenience of drug administration, an indwelling intravenous catheter (Port-A-Cath) was implanted before the start of the first chemotherapy course. Standard premedication was used to prevent paclitaxel-related hypersensitivity reaction, including dexamethasone 20 mg orally 12 hours and 6 hours before paclitaxel infusion, diphenhydramine 30 mg intravenously, and ranitidine 50 mg intravenously 30 minutes before paclitaxel infusion. Antiemetic therapy was given according to the guidelines of the American Society of Clinical Oncology.19
Chemotherapy was started on the scheduled day of treatment if the white blood cell count was ≥ 4000/μL and the platelet count was ≥ 100,000/μL. If a delay of more than 1 week was required for hemogram recovery, then the dose of paclitaxel was reduced by 20% in the next cycle. Dose reduction of cisplatin by 50% was done if a reduction ≥ 50% in creatinine clearance was found compared with the pretreatment level or if there was an elevation of the serum creatinine level ≥ 2.0 mg/dL. Further dose reduction of paclitaxel or cisplatin was not allowed. If treatment-induced toxicity failed to resolve, then the protocol treatment was discontinued.
Evaluation of Tumor Response
During protocol treatment, the patients were evaluated every week with a routine history and physical examination. Hemogram was checked weekly, and serum biochemistry and electrolyte levels were checked before each cycle of chemotherapy and as indicated clinically. Neuropathy was assessed by history and physical examination. Patients who received at least one cycle of protocol treatment were considered evaluable for toxicity, and patients who received at least two cycles of protocol treatment were considered evaluable for response. Both the response and the toxicity were evaluated according to World Health Organization criteria.20
For patients with LABC, the operability of the primary tumor was evaluated by the surgeons after maximal tumor response to chemotherapy was documented. Maximal tumor response was defined as no further tumor remission between two consecutive assessments. Surgery with curative intent was performed if the tumor was considered operable. Adjuvant chemotherapy and radiotherapy were given after the operation.21 For patients with tumors that remained inoperable after maximal tumor response, salvage treatment with local radiotherapy or second-line chemotherapy regimens was given at the discretion of the physician in charge, and the protocol treatment was discontinued.
For patients with metastatic disease, those with a complete response (CR) were given three additional courses of chemotherapy after the documentation of CR. If disease progression (PD) was noted during follow-up, then the choice of further treatment was made at the discretion of the physician in charge. Patients with a partial response (PR) continued the protocol treatment until either maximal response was achieved or prohibitive toxicity developed. Patients with PD under protocol therapy and patients with stable disease (SD) after four courses of chemotherapy were given salvage treatment, and the protocol therapy was discontinued.
Simon's optimal, two-stage, Phase II trial design was used to estimate the number of patients needed in this study.22 With a lower activity level of 30% and a higher activity level of 50%, at least 5 responders should be seen among the first 15 patients, and a total of 46 patients should be accrued for a statistical power of 80% and a false positive rate of 5%.
The time to disease progression for patients with an objective tumor response to protocol therapy was defined as the duration from the starting date of protocol therapy to the date of documented disease progression, death by any cause, or last follow-up. Overall survival was calculated from the starting date of protocol therapy to the date of patient death or last follow-up using the Kaplan–Meier method.
From July 1999 to March 2001, 47 chemotherapy-naïve patients with breast carcinoma were enrolled in this study. One patient with LABC was excluded because of a complicated malpositioning of the Port-A-Cath indwelling catheter. The clinical characteristics of the remaining 46 patients are summarized in Table 1.
|Characteristic||No. of patients|
|LABC (n = 28)||MBC (n = 18)|
|Age at diagnosis (yrs)|
|Site of metastasis|
A total of 205 courses of chemotherapy were given. All patients were evaluable for toxicity. The treatment-related toxicities are shown in Table 2. The neurotoxicity consisted of paresthesia over the extremities in all affected patients and Grade 2 hearing loss in one patient. Other toxicities were generally mild. The protocol treatment was discontinued in one patient with metastatic disease after six courses of treatment because of persistent Grade 2 leukopenia.
|Leukopenia||16 (34.8)||20 (43.5)||2 (4.3)||1 (2.2)|
|Anemia||1 (2.2)||24 (52.2)||1 (2.2)||0|
|Thrombocytopenia||0||2 (4.3)||1 (2.2)||0|
|Nausea/emesis||18 (39.1)||16 (34.8)||2 (4.3)||4 (8.7)|
|Neurosensory||32 (69.6)||7 (15.2)||1 (2.2)||0|
|Renal||11 (23.9)||2 (4.3)||0||0|
|Diarrhea||15 (32.6)||4 (8.7)||1 (2.2)||1 (2.2)|
|Fever||4 (8.7)||7 (15.2)||0||0|
|Myalgia||1 (2.2)||14 (30.4)||0||0|
|Stomatitis||15 (32.6)||2 (4.3)||0||0|
|Skin||5 (10.9)||2 (4.3)||0||0|
|Dyspnea||1 (2.2)||1 (2.2)||0||0|
|Others||2 (4.3)c||4 (8.7)d||1 (2.2)e||0|
Forty-five patients were evaluable for tumor response to paclitaxel-cisplatin chemotherapy. Of 28 patients with LABC, 2 patients achieved a CR, 14 patients achieved a PR, 11 patients had SD, and 1 patient had PD, for an objective response rate of 57.1% (95% confidence interval [95%CI], 38.8–75.4%). One of the two complete responders had pathologic CR. Of the 17 patients with MBC, 1 patient achieved a CR, 10 patients achieved a PR, 4 patients had SD, and 2 patients had PD, for a response rate of 61.1% (95%CI, 38.6–3.6%). The overall response rate for the whole group was 58.7% (95%CI, 44.5–72.9%).
Except for one patient who developed bone metastasis during protocol therapy, all of the other 27 patients with LABC underwent modified radical mastectomy after completing the protocol chemotherapy. Postoperatively, 23 patients received anthracycline-containing regimens; and 3 patients received combined cyclophosphamide, methotrexate, and fluorouracil as adjuvant chemotherapy. One patient received adjuvant tamoxifen alone. Tamoxifen also was given to 12 patients who had positive estrogen receptor status after the completion of adjuvant chemotherapy. Eighteen patients received adjuvant radiotherapy.
The median follow-up for the 28 patients with LABC was 16 months (range, 6.3–30.9 months). Five patients had disease progression, with local recurrence in one patient, bone metastasis in one patient, malignant pleural effusion in one patient, and lung and liver metastases in two patients. The median time to disease progression was 14.8 months (range, 3.9–16.6 months). Two patients died of disease progression 10.0 months and 18.2 months after the start of protocol therapy.
The median follow-up for the 18 patients with MBC was 14.6 months (range, 3.2–30.9 months). Six patients (one patient who achieved a CR, four patients who achieved a PR, and one patient with SD) changed to tamoxifen therapy, and one patient (who achieved a PR) received radiotherapy after maximal response was achieved. Five patients (two patients who achieved a PR, two patients with SD, and one patient with PD) received salvage chemotherapy. Four patients (three patients who achieved a PR and one patient with SD) had disease progression under protocol therapy. Three patients died of PD 3.2 months, 20.4 months, and 30.9 months after the start of protocol therapy. The Kaplan–Meier method was used to estimate overall survival and progression free survival, as shown in Figure 1.
This study demonstrated that a regimen of paclitaxel 175 mg/m2 by 3-hour infusion plus cisplatin 50 mg/m2 by 24-hour infusion in a 3-week cycle was an effective and well-tolerated regimen for chemotherapy-naïve patients with breast carcinoma. The incidence of Grade 3 or greater gastrointestinal toxicity, neuropathy, and myelosuppression in this study was relatively low compared with other of studies using similar regimens for the treatment of various types of malignancies.13–15, 23–25 This supports our hypothesis that the use of 24-hour infusions of cisplatin may reduce treatment-related toxicities without hampering its antitumor activity.
Several groups have studied the combination of paclitaxel and cisplatin for the treatment of patients with breast carcinoma. Gelmon et al. reported a response rate of 85% in a Phase I–II trial of 29 patients with MBC and no prior chemotherapy for Stage IV disease.13 A biweekly schedule with paclitaxel 90 mg/m2 and cisplatin 60 mg/m2, both by 3-hour infusion, was used in that Phase II trial due to dose-limiting neutropenia. However, the same regimen produced a response rate of only 23% in 16 patients with prior chemotherapy.14 Wasserheit et al. conducted a Phase II trial in 44 patients with LABC or MBC who had received no more than one previous chemotherapy regimen.15 Paclitaxel 200 mg/m2 was given by 24-hour infusion followed by cisplatin 75 mg/m2 by bolus injection: Prophylactic granulocyte-colony stimulating factor was given routinely, and the overall response rate was 48.5%. In that study, it was found that cumulative neurotoxicity was dose limiting, and 50% of the patients were removed from the study after they developed neurotoxicity.
The activity and toxicity of combination therapy with paclitaxel and cisplatin are dose and schedule dependent.26 In vitro data as well as in vivo data indicate that the sequence of paclitaxel followed by cisplatin is both more active and less toxic.27 By contrast, the administration of cisplatin before paclitaxel demonstrated antagonistic effects in cell cultures.28 Paclitaxel stabilizes tubulin polymerization, resulting in cell cycle arrest in the G2-M phase and the induction of apoptosis. Thus, tumor cells are most susceptible to paclitaxel in the G2-M phase. Cisplatin binds to cellular DNA and produces DNA cross links, leading to inhibition of DNA replication and cell cycle arrest at the G2 phase. The antagonistic effect of cisplatin followed by paclitaxel may be secondary to the G2 arrest induced by cisplatin and probably interference with tubulin or tubulin-associated proteins by cisplatin.29, 30 In addition, cisplatin may decrease paclitaxel clearance and, thus, may increase paclitaxel toxicity.31 Recently, Ezzat et al. reported a novel circadian schedule of a 3-hour infusion of paclitaxel 135 mg/m2 followed 12 hours later by a 1-hour infusion of cisplatin 75 mg/m2 for patients with breast carcinoma.32, 33 A response rate of 90% was demonstrated both for patients with LABC and for patients with MBMC, and the regimen appeared to be well tolerated. These results support the hypothesis of a schedule dependent, synergistic effect between paclitaxel and cisplatin. Further studies exploring the optimal dose schedule of this combination and randomized clinical trials to confirm the clinical efficacy are necessary.
Patients who present with LABC usually are treated in a multimodality approach with chemotherapy and radiotherapy or surgery. Preoperative chemotherapy has several theoretical advantages.34 It permits the use of the primary tumor to monitor response to treatment and may produce less favorable growth kinetics for micrometastases. Data from randomized studies indicate that preoperative chemotherapy resulted in a high response rate and an increase in breast-conserving treatment.35–37 Conversely, no significant increase was found in disease free survival or overall survival with the use of preoperative chemotherapy. The addition of taxane to anthracycline-based adjuvant chemotherapy regimens may improve the disease free survival and overall survival of patients with lymph node positive breast carcinoma, although a definite recommendation for therapy cannot be made, because the follow-up from large randomized trials still is limited.38, 39 Our experience suggests that the addition of chemotherapy with paclitaxel and cisplatin to an anthracycline-based adjuvant regimen is feasible. Its full therapeutic potential in the adjuvant setting remains to be investigated. In conclusion, our data suggest that paclitaxel 175 mg/m2 by 3-hour infusion plus cisplatin 50 mg/m2 by 24-hour infusion is an active and well-tolerated chemotherapy regimen for the treatment of chemotherapy-naïve patients with breast carcinoma.
- 12Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000; 18: 623–631., , , et al.
- 18American Joint Committee on Cancer. Manual for staging of cancer. 4th ed. Philadelphia: JB Lippincott, 1992: 149–152.
- 22Design and conduct of clinical trials. In: DeVitaVT, HellmanS, RosenbergSA, editors. Cancer: principles and practice of oncology, 4th edition. Philadelphia: Lippincott; 1993: 418–440..
- 38Improved disease-free survival (DFS) and overall survival (OS) from the addition of sequential paclitaxel (T) but not from the escalation of doxorubicin (A) dose level in the adjuvant chemotherapy of patients (PTS) with node-positive primary breast cancer (BC) [abstract]. Proc Am Soc Clin Oncol. 1998; 17: 101., , , et al.