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© 2002 American Society for Clinical Oncology Time to Progression in Metastatic Breast Cancer Patients Treated With Epirubicin Is Not Improved by the Addition of Either Cisplatin or Lonidamine: Final Results of a Phase III Study With a Factorial DesignByFrom Oncologia Medica, Azienda Ospedaliera San Luigi, Orbassano; Centro di Senologia, Azienda Ospedaliera Istituti Ospitalieri, Cremona; Endocrinologia Oncologica, Istituto Tumori Fondazione Pascale, Napoli; Clinica Ostetrica e Ginecologica, Azienda Ospedaliera Sant’Anna; Ginecologia Oncologica, Azienda Ospedaliera Sant’Anna; and Oncologia Medica Ospedale San Giovanni, Torino; Oncologia Medica, Istituto Oncologico, Bari; Oncologia Medica, Istituto Clinica Medica Universitaria, Sassari; Chirurgia Generale IV, Azienda Ospedaliera San Giovanni Battista; Oncologia Medica, Ospedale San Lazzaro, Alba; Radioterapia, Ospedale degli Infermi, Biella; Ginecologia, Ospedale SS Annunziata, Savigliano; and Servizio di Epidemiologia Clinica, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy. Address reprint requests to Luigi Dogliotti, MD, PhD, Oncologia Medica, Azienda Ospedaliera San Luigi, Regione Gonzole 10, 10043 Orbassano, Torino, Italy; email: luigi.dogliotti{at}unito.it
PURPOSE: To investigate the value of the addition of either cisplatin (CDDP) or lonidamine (LND) to epirubicin (EPI) in the first-line treatment of advanced breast cancer. PATIENTS AND METHODS: Three hundred seventy-one metastatic breast cancer patients with no prior systemic chemotherapy for advanced disease were randomized to receive either EPI alone (60 mg/m2 on days 1 and 2 every 21 days), EPI and CDDP (30 mg/m2 on days 1 and 2 every 21 days), EPI and LND (450 mg orally daily, given continuously), or EPI, CDDP, and LND. Time to progression, response rates, side effects, and survival were compared according to the 2 x 2 factorial design of this study. RESULTS: The groups were well balanced with respect to prognostic factors. Time to progression did not differ in the comparison between CDDP arms and non-CDDP arms (median, 10.9 months v 9.4 months, respectively; P = .10) or between that of LND arms and non-LND arms (median, 10.8 months v 9.9 months, respectively; P = .47), nor did overall survival. The response rate did not significantly differ in the comparison between LND arms and non-LND arms (62.9% v 54.0%, P = .08). No difference in treatment activity was observed between CDDP arms and non-CDDP arms. Toxicity was significantly higher in the CDDP arms, leading to CDDP dose adjustment in 40% of cases. The most frequent side effects were of a hematologic and gastrointestinal nature. The addition of LND produced more myalgias and fatigue. CONCLUSION: Neither CDDP nor LND was able to significantly improve the time to progression obtained by EPI. CDDP, however, significantly worsened the drug’s tolerability.
BREAST CANCER remains the first cancer cause of death among women in Italy.1 There is no known treatment that seems to substantially prolong the disease-free or overall survival of metastatic breast cancer patients.2,3 Anthracyclines are widely recognized as the most active drugs, with response rates ranging from 40% to 60% in advanced disease.4,5 Anthracyclines, however, failed to cure metastatic disease, with cellular resistance being the major cause of treatment failure. Lonidamine (LND) is a nonconventional anticancer drug that has no effect on cellular DNA, RNA, or protein synthesis but strongly inhibits energy metabolism6-8 and modifies the permeability of cell membranes.9 Given its particular mechanism of action, LND seems to be an ideal candidate for combination with chemotherapy. Experimental studies have demonstrated the ability of LND to increase the cell-killing effect of anticancer drugs, including anthracyclines.10-13 In particular, a complete reversal of doxorubicin resistance has been obtained after combined exposure to LND in a multidrug-resistant breast cancer cell line.14,15 In a phase III study, our group showed that the activity of single-agent epirubicin is significantly enhanced by concomitant LND administration.16 Similar results have been obtained by other studies, where LND was combined with anthracyclines, cyclophosphamide, and fluorouracil.17-20 In our study, however, the significant increase in response rate did not result in a corresponding increase of overall time to progression. This latter finding contrasted with the results of a randomized study comparing the anthracycline, cyclophosphamide, and fluorouracil regimen alone with the same regimen administered in association with LND.17 However, LND administration in our study was stopped at the end of chemotherapy, whereas in the other study it was continued until progression. This difference in LND schedule administration could have accounted for the discrepancy in the time to progression observed. There is now considerable literature on the role of cisplatin either as a single agent or in combination chemotherapy in previously untreated advanced breast cancer patients.21 Recently, promising results have been obtained with cisplatin-containing schemes as second-line treatment.22-25 However, most published studies are uncontrolled and often involve small patient samples. Five randomized trials compared cisplatin combination chemotherapy with conventional regimens.26-30 These trials showed that first-line combination chemotherapy with cisplatin may achieve higher response rates than conventional schedules, without significant benefits in response duration. Because of the relatively few cases included in each study, however, the findings on time to progression and overall survival are inadequate. LND was recently found to be able to modulate the cytotoxic activity of cisplatin associated with epirubicin in two human breast cancer cell lines.31 We therefore conducted a pilot study to determine the activity of the combination of cisplatin with epirubicin and LND.32 The results obtained with this cytotoxic regimen were noteworthy: an 82% response rate in assessable patients was achieved, but with substantial toxicity. In order to demonstrate whether the addition of cisplatin or LND could increase the efficacy of epirubicin in the treatment of advanced breast cancer patients, we tested epirubicin against epirubicin and LND, epirubicin and cisplatin, and epirubicin, cisplatin, and LND in a randomized phase III trial with factorial design. Because of the previous toxicity, the cisplatin dose was reduced.
Patients Patients with measurable or assessable (according to World Health Organization [WHO] criteria33) and histologically proven metastatic breast cancer were considered eligible. Prior systemic chemotherapy for advanced disease was not allowed, but one endocrine therapy line was admitted. Patients were required to have an Eastern Cooperative Oncology Group performance status  2, adequate bone marrow reserve (WBC count  3.5 x 109/L, platelets 100 x 109/L, and hemoglobin 10 g/dL) and renal function (measured creatinine clearance 60 mL/min), and an estimated life expectancy of at least 12 weeks. Patients with nonmalignant systemic disease that precluded them from receiving study therapy (eg, active infection, any clinically significant cardiac arrhythmia, congestive heart failure, complete bundle branch block functional New York Heart Association class III or worse, or pregnancy) were not eligible. Patients with CNS metastases or second primary malignancies (except in situ carcinoma of the cervix or adequately treated basal cell carcinoma of the skin), or who used any investigational agent 1 month before enrollment, were also not eligible. Previous treatments with anthracyclines or mitoxantrone-containing schemes administered in an adjuvant setting were permitted, provided that progression occurred more than 12 months from the end of such treatments. The study was approved by the local ethical committee. Written informed consent was obtained from all patients before randomization.
Treatment Schedule
Recommended treatment modifications for hematologic toxicities were as follows: 1-week delay was introduced if granulocyte counts were less than 1.5 x 109/L (or WBC counts < 3 x 109/L) and/or platelet counts were less than 100 x 109/L on day 21; after 1 week, if hematologic parameters did not recover, a dose reduction of 50% was applied when granulocyte counts ranged between 1.0 and 1.5 x 109/L (or WBC counts ranged between 2.0 and 3.0 x 109/L) and/or platelet counts ranged between 75 and 100 x 109/L. In case of lower hematologic values the following week, a further 1-week delay was allowed. Patients went off study if the delay exceeded 4 weeks. Delays and dose reductions were also allowed for grade
Treatment Evaluation The following tests were evaluated before entry onto the study: medical history and physical examination, performance status, weight, hemoglobin and hematocrit levels, and WBC and platelet count; alkaline phosphatase, ALT, AST, and bilirubin levels; serum electrolytes and serum creatinine levels; ECG; echocardiography; tumor markers (carcinoembryonic antigen, CA 15-3); chest radiograph; isotope bone scan with radiographs of abnormal areas; abdominal ultrasonography; and computed tomography scan of the chest and abdomen if necessary. Physical examination and hematologic profile were repeated before each course of chemotherapy, whereas a complete blood cell count was recommended at the nadir of leukocytes and platelets (10 to 12 days from EPI and CDDP administration).
Time to progression was defined as the time elapsed from randomization until disease progression or death. Overall survival was measured from the date of randomization until death. Standard criteria (WHO) were used for classifying response33: a complete response was defined as the complete disappearance of all clinically detectable soft-tissue and visceral malignant disease, as measured by physical examination or radiography studies, and the complete recalcification of all osteolytic lesions for at least 4 weeks. A partial response was characterized as a decrease of Response was evaluated after three treatment cycles or earlier if clinically indicated because of suspected progressive disease. Patients that experienced early treatment failure were assumed to be nonresponders. Patients received treatment for a maximum of six to eight cycles (the maximum-tolerated EPI dose), unless progressive disease or unacceptable toxicity developed, or the patient or attending physician requested discontinuation. Safety evaluations included summaries of chemotherapy, including dose adjustments, dose-intensity and details of any toxicity, and deaths or discontinuation because of study drug toxicity. All toxicities were graded using the WHO scale.33
Statistical Methods
Comparisons of treatment activity and toxicity among groups were performed by the
The study was open for enrollment between October 1995 and April 1999, when 371 patients were enrolled from 17 different institutions. Of the 371 patients enrolled, 93 were randomized onto the EPI arm, 92 onto the EPI-CDDP arm, 93 onto the EPI-LND arm, and 93 onto the EPI-CDDP-LND arm. Three patients randomized onto the EPI-CDDP-LND arm erroneously received EPI alone (one patient) or EPI-LND (two patients); two patients randomized onto the EPI-CDDP arm received EPI-CDDP-LND and EPI-LND, respectively; one patient randomized onto the EPI arm received EPI-CDDP. All these patients were considered in the statistical analysis on the arm to which they were assigned. One patient was ineligible because of the presence of primary liver cancer, erroneously interpreted as a liver metastasis. A total of 370 patients were therefore fully eligible. The major clinical characteristics of randomized patients were well balanced among the four arms (Table 1).
Treatment Efficacy The last follow-up examination was March 2001, when 318 patients (85.7%) of the 371 enrolled had progression of disease and 207 patients (56.0%) had died. TTP was similar for LND arms (median, 10.8 months; 95% CI, 9.4 to 12.2 months) versus non-LND arms (median, 9.9 months; 95% CI, 8.6 to 11.2 months) (P = .47) (Fig 1A), and CDDP arms (median, 10.9 months; 95% CI, 9.4 to 12.4 months) versus non-CDDP arms (median, 9.4 months; 95% CI, 7.7 to 10.9 months) (P = .10) (Fig 1B). Patients randomized to receive CDDP had a survival prospect (median, 28.8 months; 95% CI, 24.9 to 32.7 months) comparable to those randomized to not receive CDDP (median, 29.5 months; 95% CI, 23.5 to 35.5 months). Overall survival was also comparable in LND arms (median, 29.8 months; 95% CI, 27.5 to 32.2 months) versus non-LND arms (median, 27.3 months; 95% CI, 23.7 to 30.9 months), respectively. TTP and overall survival distributions for LND and non-LND arms did not change after adjustment for CDDP; similarly, TTP and survival of CDDP and non-CDDP arms did not differ after adjustment for LND.
The log-rank P value for testing equality of TTP over the four treatment groups was .23 (Fig 2). The study, however, is not designed to address the four-arm comparison.
A statistical test for interaction between CDDP and LND for TTP variable was performed, and no significant interaction was found (odds ratio [OR], 1.29; 95% CI, 0.83 to 2.04; P = .256). The OR of CDDP, LND, and interaction of both drugs was not significant, even after adjustment for major prognostic variables (Table 2).
Analysis of response was performed considering all registered patients according to an ITT (Table 3). Twenty-nine patients (7.8%) were not assessable for response. The reasons for not being assessable were as follows: early death in six patients (three randomized on the EPI-CDDP-LND arm, one on the EPI-LND arm, and two on the EPI arm); toxicity in four patients (two on the EPI-CDDP-LND arm, one on the EPI-LND arm, and one on the EPI arm); and treatment refusal or lost to follow-up before the first response evaluation was recorded in five patients randomized on the EPI, four on the EPI-LND arm, five on the EPI-CDDP arm, and five on the EPI-CDDP-LND arm.
The response rate of the LND-containing regimens was slightly higher than those not containing LND. This difference just failed to be statistically significant. No significant difference was observed between the response rate of CDDP arms and non-CDDP arms. As for TTP, a statistical test for LND and CDDP interaction was performed and was not significant (OR, 0.78; 95% CI, 0.34 to 1.81; P = .573).
In the single arms, the highest response rate was obtained on the EPI-CDDP-LND arm, and the lowest was obtained on the EPI arm (Table 3). The differences among single treatment arms failed to be statistically significant by the
Treatment Received
Toxicity Details of toxicity are listed in Tables 5 and 6 and are expressed as the worst toxicity for any course reported during the treatment period for all patients who started the treatment (N = 363). As a whole, regimens containing CDDP were considerably more toxic than those without CDDP. Grade 3 to 4 hematologic toxicity, evaluated either at nadir or at the retreatment day (first day of the next cycle), was significantly higher in patients who received CDDP than in those who did not (P < .03 for WBC at time of next cycle, P < .001 for WBC at nadir, and P < .001 for platelets both at nadir and at time of next cycle). No difference in hematologic toxicity was found when LND and non-LND arms were compared. Among the nonhematologic side effects, CDDP administration but not LND use was associated with a greater frequency of grade 3 to 4 mucositis (P < .05). In contrast, LND assumption was associated with greater grade 3 to 4 fatigue (P < .001) and grade 3 to 4 myalgias (P < .001). Concerning cardiotoxicity, five patients developed clinical congestive heart failure: one patient on the EPI arm, one on the EPI-CDDP arm, one on the EPI-LND arm, and two on the EPI-CDDP-LND arm. However, sporadic measurement of left-ventricular ejection fraction precluded detailed assessment of cardiotoxicity. Eleven patients suffered toxic death (3.0%): three on the EPI arm, three on the EPI-CDDP arm, two on the EPI-LND arm, and three on the EPI-CDDP-LND arm. The causes of toxic death were septic shock caused by hematologic toxicity in two cases, pulmonary thromboembolism in one, sudden death in three, hepatic toxicity in one, congestive heart failure in two, arrhythmia in one, and hepatorenal syndrome in one. Six of these adverse events occurred after one chemotherapy cycle, one occurred after three chemotherapy cycles, one occurred after four chemotherapy cycles, two occurred after five cycles, and the last one occurred 1 month after the end of the sixth cycle.
Data mainly from phase II studies or small phase III trials published so far have suggested a possible role of CDDP in combination chemotherapy in previously untreated metastatic breast cancer.21 Randomized studies have shown that the addition of LND to EPI-containing regimens can improve the response rate.16,17,20 However, the latter studies did not provide enough statistical power to detect difference in time to progression and overall survival. The 2 x 2 factorial design of the present study allowed us to test simultaneously whether CDDP or LND is able to significantly affect the efficacy of single-agent EPI in metastatic breast cancer patients. The results of the study, in which all treatment arms were well balanced with respect to the major prognostic factors, show that neither CDDP nor LND was able to significantly prolong the TTP of advanced breast cancer patients who received EPI. This statement was also supported by the overlapping 95% CI. Multivariate analyses showed that LND and CDDP do not act synergistically with respect to TTP, even adjusting for major prognostic parameters. Of course, we are not able to exclude that significant differences in TTP between arms could have been obtained if a greater number of patients had been included in the study. Overlapping CIs, in fact, do not necessarily provide strong evidence of lack of effect and the CIs for the CDDP versus no-CDDP arms and LND versus no-LND arms, provided in the multivariate model (Table 2), suggest that differences of interest may not be ruled out. Our data further confirm the activity of single-agent EPI administered at 120 mg/m2 in metastatic breast cancer. The overall response rate (50.6%) is similar to that obtained by other studies in which EPI was given at the same dose.35 Interestingly, this response rate was also similar to published data on anthracycline-containing regimens generally used as first-line chemotherapy.36,37 On this basis, 120 mg/m2 through IV bolus administration every 3 weeks represents the reference dose for the use of EPI as a single agent in breast cancer patients. To ensure the equivalence of all treatment arms for anthracycline exposure, we chose to maintain EPI at 120 mg/m2 also on the CDDP arms. The mean cumulative dose of EPI administered on the CDDP arms was not dissimilar to that on the non-CDDP arms. However, the delivered full-dose EPI could have limited the CDDP dose. The planned CDDP dose of 60 mg/m2 in our study is low/moderate, and was further reduced because of toxicity in 40% of patients and in 25% of cycles. The low CDDP dose effectively delivered may have accounted in part for the lack of increased efficacy. We observed a statistically significant difference in toxicity, noting that CDDP regimens were more toxic. The addition of CDDP to EPI produced more bone marrow depression in platelets and hemoglobin, and increased mucositis. Although the drug toxicity–related mortality rate did not differ between the CDDP arms and the non-CDDP arms, increased toxicity made CDDP an awkward drug in this area of palliative medicine. The present study fails to confirm the results of our previous experience, as the addition of LND to EPI led to only a small (nonsignificant) improvement in response rates. Patient selection and the addition of CDDP could account at least in part for the differences encountered between the present study and the previous one.16 Toxicity, however, was not consistently affected, except for fatigue and myalgias. Similar to our previous experience, the absence of any effect of LND administration in prolonging time to progression and overall survival of patients who received EPI may suggest that LND is unable to influence anthracycline effectiveness. In conclusion, the results of this randomized study confirm the activity of EPI as a single agent in metastatic breast cancer patients. The addition of CDDP to full-dose EPI did not result in a significant increase in TTP, but significantly worsened treatment tolerability, thus failing to demonstrate a better risk/benefit ratio with respect to EPI alone. LND administration did not consistently affect the toxicologic profile of EPI with or without CDDP. However, the absence of any favorable effect on TTP and overall survival suggests that the drug does not seem to contribute to the effectiveness of anthracycline-based chemotherapy for advanced breast cancer. These results did not change when the comparison between CDDP arms was adjusted for LND and the comparison between the LND arms was adjusted for CDDP.
APPENDIX The appendix listing EPI-LON group organization and trialists is available online at www.jco.org.
We thank Franco Berruti for help in the data management of the study.
Presented in part at the Thirty-Sixth Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, May 19-23, 2000.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. A test for interaction between the two factors (CDDP and LND) for the treatment response was performed using a logistic model. Duration of time to progression (TTP) and overall survival curves were estimated using the Kaplan-Meier method. Data were expressed as median ± 95% coefficient interval (CI). Greenwood’s formula was used to calculate the 95% CI.
