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© 2003 American Society for Clinical Oncology Addition of Either Lonidamine or Granulocyte Colony-Stimulating Factor Does Not Improve Survival in Early Breast Cancer Patients Treated With High-Dose Epirubicin and CyclophosphamideFrom the Departments of Medical Oncology and Surgery, Regina Elena Cancer Institute; Division of Medical Oncology, University "La Sapienza", School of Medicine; Division of Medical Oncology, S Filippo Neri Hospital; Division of Medical Oncology, S Eugenio Hospital; Division of Medical Oncology, S Camillo Hospital; and Division of Medical Oncology, Catholic University School of Medicine, Rome, Italy. Address reprint requests to Paola Papaldo, MD, Division of Medical Oncology "A," Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy; email: p.papaldo{at}mclink.it.
Purpose: Lonidamine (LND) can enhance the activity of anthracyclines in patients with metastatic breast cancer. A multicenter, prospective, randomized trial was designed to determine whether the association of LND with high-dose epirubicin plus cyclophosphamide (EC) could improve disease-free survival (DFS) in patients with early breast cancer (BC) compared with EC alone. Granulocyte colony-stimulating factor (G-CSF) was added to maintain the EC dose-intensity. Patients and Methods: From October 1991 to April 1994, 506 patients with stage I/II BC were randomly assigned to four groups: (A) epirubicin 120 mg/m2 and cyclophosphamide 600 mg/m2 administered intravenously on day 1 every 21 days for four cycles (124 patients); (B) EC plus LND 450 mg/d administered orally (125 patients); (C) EC plus G-CSF administered subcutaneously (129 patients); (D) EC plus LND plus G-CSF (128 patients). Results: Median follow-up was 55 months. Five-year DFS rate was similar for LND (B+D groups; 69.6%) versus non-LND arms (A+C groups; 70.3%) and G-CSF (C+D groups; 67.2%) versus non–G-CSF arms (A+B groups; 72.9%). Five-year overall survival (OS) was comparable in LND (79.1%) versus non-LND arms (81.3%) and in G-CSF (80.6%) versus non–G-CSF arms (79.6%). DFS and OS distributions in LND and G-CSF arms did not change according to tumor size, node, receptor, and menopausal status. G-CSF dramatically reduced hematologic toxicity without having a significant impact on dose-intensity (98.1% v 95.5% for C+D and A+B groups, respectively). Conclusion: EC is active and well tolerated in patients with early breast cancer. The addition of LND or G-CSF does not improve DFS or OS.
BECAUSE THE goal of therapy for metastatic breast cancer (BC) is still palliation, whereas for early BC the goal is cure, the most efficient chemotherapy regimen should be offered in the adjuvant setting. For this reason, based on the increasing demand for more active and less toxic anticancer treatments, several compounds have been investigated with the aim of increasing the efficacy of current antineoplastic drugs. Promising results with resistance modulation have been obtained in the laboratory setting using the energolytic derivative of indazole-carboxylic acid known as lonidamine (LND), which has proven to be capable of reversing resistance to anthracyclines, one of the most active agents against BC. Resistance to anthracyclines is a multifactorial mechanism, often mediated by the overexpression of an energy-dependent membrane pump called P-glycoprotein and encoded by a multidrug resistance gene. LND is able to inhibit cellular energy metabolism and potentially increase the damage induced by antineoplastic agents.1–12 The underlying mechanisms include the blockade of anaerobic glicolysis, the inhibition of lactate transport with subsequent intracellular acidification, and the permeability of cellular membranes with an increased drug uptake. The ability of LND to modulate the cytotoxic activity of anthracyclines has been widely investigated in vitro.13–18 The uptake of doxorubicin (ADM) is greatly stimulated by LND, and the increase depends on the energy sources of the cell.13 ADM-resistant breast cancer cells exposed to LND showed a change in the electrical charge distribution across the plasma membrane and a time-dependent reduction of P170 phosphorylation. These effects were associated with a marked increase in intracellular ADM accumulation in resistant cells.16 It has been reported that LND reverses ADM and cyclophosphamide resistance in previously treated patients with metastatic BC and significantly improves the activity of single-agent epirubicin administered as first-line treatment for patients with advanced BC.19,20 In our previous experience, the regimen of fluorouracil, ADM, and cyclophosphamide with or without LND was evaluated in the metastatic setting. The response rate was 62% in the LND arm versus 46.7% in the control arm (P = .002). Time to progression was significantly longer in the LND arm (9.2 v 6.3 months; P = .003), but overall survival did not significantly differ in both arms, except for in postmenopausal patients, who experienced increased survival with the addition of LND (18.9 v 14.8 months; P = .018).21 At the end of the 1980s, preclinical findings, together with the evidence reported for advanced BC, prompted us to test the addition of LND to cyclophosphamide and high-dose epirubicin (EC) in patients with early BC. We also added granulocyte colony-stimulating factor (G-CSF) with the goal of maintaining the EC dose-intensity, as most chemotherapeutic drugs exhibit a dose-response pattern for cytotoxicity. We thought that administering G-CSF to prevent myelosuppression would increase chemotherapeutic drug doses, potentially improving disease-free and overall survival rates. To enhance the therapeutic efficacy in anthracycline-sensitive tumors, such as breast carcinoma, the dose intensification of epirubicin in the adjuvant setting was justified, because when it was used in high-dose regimens either as a single agent or in combination with other cytotoxic drugs, response rates were significantly improved in most studies, with acceptable toxicity and no increase in cardiac risk.22–25 To demonstrate whether the addition of LND or G-CSF could increase the efficacy of EC in the treatment of patients with early BC, we tested EC with or without LND or G-CSF in a randomized phase III trial with a 2 x 2 factorial design with the intent to compare the control with LND and G-CSF arms.
Patients The eligibility criteria were as follows: age 18 to 65 years; histologically confirmed diagnosis of BC; stage I disease with tumor greater than 1 cm in the greatest diameter or stage II disease; receptor positive and receptor negative tumor for premenopausal women and receptor negative tumor for postmenopausal women; adequate bone marrow reserve (WBC count  4.0 x 109/L, platelets 100 x 109/L); normal hepatic and renal function (measured creatinine clearance 60 mL/min); normal left ventricular ejection fraction (LVEF); no history of active infection, clinically significant cardiac arrhythmia, congestive heart failure, or uncontrolled hypertension; no pregnancy; no previous or concurrent malignancies of other sites (except in situ carcinoma of the cervix or adequately treated basal cell carcinoma of the skin). The study was approved by an independent ethics committee. Oral informed consent was obtained from all patients before randomization.
Treatment Plan
Prophylactic antiemetic therapy with 5HT3 antagonist plus dexamethasone was allowed. For all patients treated with conservative surgery, locoregional radiation therapy was started after completion of cytotoxic therapy. 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, lactate dehydrogenase, ALT, AST, and bilirubin levels; serum electrolytes and serum creatinine levels; ECG and LVEF; chest x-ray; isotope bone scan with radiographs of abnormal areas; abdominal ultrasonography; and computed tomography scan of the chest and abdomen, if necessary. Physical examination, hematologic profile, and ECG were repeated before each course of chemotherapy, whereas a complete blood cell count was performed weekly (on days 7, 14, and 21) in each group. LVEF was assessed before the third cycle, 21 days after the fourth cycle, and during follow-up if indicated. The therapy was discontinued in case of disease progression, patient refusal of further treatment, LVEF reduction Recommended treatment modifications for hematologic toxicities were as follows: in case of myelosuppression (neutrophil count < 2,000/µL and platelets count < 100,000/µL), chemotherapy was delayed weekly until recovery; patients were removed from the study if the delay exceeded 6 weeks. Myalgia, gastric pain, and asthenia were graded as mild, moderate, or severe. All other toxicities were graded using the World Health Organization scale. A 25% reduction of the total dose was planned when neutropenic fever occurred, in the event of grade 4 neutropenia or thrombocytopenia lasting for more than 6 days, or in the event of an infectious episode (fever associated with confirmed or suspected infection, fever resulting in hospitalization, or antibiotics given for a documented infection). Delays and dose reductions were also allowed for grade 3 or worse stomatitis and renal impairment (creatinine clearance < 60 mL/min). G-CSF was not allowed out of protocol indications. The LND dose reduction was planned at 300 mg/d if moderate drug-related adverse effects occurred (myalgia, gastric pain). If symptoms of toxicity persisted, LND was further reduced to 225 mg/d. In case of severe toxicity, LND was discontinued.
Treatment Evaluation
Statistical Methods
Between October 1991 and April 1994, six institutions enrolled 506 women onto this trial, of whom 124 were randomly assigned to the EC arm, 125 to the EC plus LND arm, 129 to the EC plus G-CSF arm, and 128 to the EC plus LND plus G-CSF arm. The patients and tumor characteristics (Table 1  ) were well balanced among the groups. Nine patients were not assessable for DFS and OS because of no treatment administration (two patients), ineligibility (two patients), refuse after one cycle (two patients), missing data (two patients), and cardiac toxicity after one cycle (one patient). Toxicity data were inadequate for five patients. The results for the 497 assessable patients are reported in Tables 1 through 4.
Treatment Efficacy Five-year DFS and 5-year OS rates for all patients were 69.9% and 79.5%, respectively (median follow-up, 55 months) The last follow-up examination was April 1998, when 147 patients (29.6%) of the 497 enrolled had recurrence of disease, and 88 patients (17.7%) had died. Five-year DFS rate was similar for LND arms (B and D groups; 69.6%; 95% CI, 63.5% to 75.7%) versus non-LND arms (A and C groups; 70.3%; 95% CI, 64.4% to 76.2%; P = .98; Fig 1 ) and G-CSF arms (C and D groups; 67.2%; 95% CI, 61.1% to 73.3%) versus non–G-CSF arms (A and B groups; 72.9%; 95% CI, 67.2% to 78.6%; P = .21). Five-year OS was also comparable in LND arms (79.1%; 95% CI, 73.2% to 85.0%) and non-LND arms (81.3%; 95% CI, 75.8% to 86.8%; Fig 2) and in G-CSF arms (80.6%; 95% CI, 74.9% to 86.3%) versus non–G-CSF arms (79.6%; 95% CI, 73.9% to 85.3%). DFS and OS distributions in LND and non-LND arms did not change after adjustment for G-CSF; similarly, DFS and OS in G-CSF and non–G-CSF arms did not differ after adjustment for LND, even according to tumor size, node, receptor, and menopausal status. As expected, significantly higher DFS and OS were observed in patients with tumors less than 2 cm versus those with tumors greater than 2 cm (P < .00001 and P = .0003, respectively) and in patients with zero to three involved nodes versus patients with more than three involved nodes (P < .00001 and P < .00001, respectively). No significant differences were observed between patients with no involved nodes and patients with one to three nodes (Table 3 ). Seventeen patients developed new malignancies during follow-up: 12 developed contralateral breast cancer, one developed acute myeloid leukemia M5 (arm EC + G-CSF), one developed ovarian cancer, one developed urothelial cancer, one developed colon cancer, and one developed melanoma.
Treatment Received The dose-intensity was comparable in LND arms and non-LND arms. LND administration did not influence the administered dose of either EC or G-CSF. All patients on G-CSF arms and 96% of those on non–G-CSF arms remained on study throughout the four cycles scheduled. A total of 963 and 961 cycles of therapy were delivered in the G-CSF arms and non–G-CSF arms, respectively. The rate of delayed cycles was 3.6% in the G-CSF arms and 10% in the control arms (P < .0001); the frequency of dose reduction was 1.4% and 3.6% in G-CSF and control arms, respectively (P = .002). The EC dose-intensity was greater in the G-CSF arms than in the control arms (98.1% v 95.5% of the planned dose-intensity, respectively), though this was not statistically significant.
Toxicity
LND treatment was associated with myalgia, gastric pain, and asthenia in 24.7%, 16.5%, and 3.3% of patients, respectively; the above toxicities were severe in 3.3%, 16.5%, and 0.4% of cases, respectively. Dose reduction and discontinuation were observed in 16.1% and 9% of patients, respectively (Table 5
Concerning cardiotoxicity, all cardiac disturbances were fully reversible after completing chemotherapy, as demonstrated by ECG and LVEF measurement. During EC, nine patients showed aspecific repolarization abnormalities, with two patients’ ECG findings resembling subendocardial ischemia, one patient’s findings suggesting sinus tachycardia, and six patients’ findings indicating an LVEF decrease of greater than 20% after the fourth cycle of chemotherapy, with a complete recovery during follow-up. Nausea was reported in 30.4% of the patients, and grade 3 vomiting occurred in 13.2% of patients. Other toxicities were severe asthenia (0.8%) and grade 3 diarrhea (0.4%). All patients presented grade 3 alopecia.
The 2 x 2 factorial design of the present study allowed us to test simultaneously whether LND or G-CSF were able to significantly affect the efficacy of EC in patients with early BC. The results of the study, in which all treatment arms were well balanced with respect to the major prognostic factors, show that neither LND nor G-CSF was able to significantly prolong the DFS of patients with early BC who received EC. Multivariate analyses showed that LND and G-CSF do not act synergistically with respect to DFS, even adjusting for major prognostic parameters. Randomized studies have shown that the addition of LND to epirubicin-containing regimens can improve the response rate20,26 without providing enough statistical power to detect difference in time to progression and OS. This is the first randomized trial reported to date exploring the association of LND with anthracycline-based chemotherapy in patients with early BC. Despite our previous data in patients with advanced BC treated with fluorouracil, ADM, and cyclophosphamide,21 showing an advantage in OS for postmenopausal women, in the present trial, patients with early BC who received LND did not obtain any improvement of either DFS or OS regardless of menopausal status. In terms of toxicity, there was no difference between the LND and control arms with the exception of myalgia, which was significantly higher in patients who received LND and G-CSF. It is noteworthy that in patients with metastatic BC, Amadori et al26 failed to show a significant difference in overall response rate by adding LND to ADM, whereas Dogliotti et al,20 even observing that the combination of epirubicin plus LND resulted in a significant improvement of responses in comparison with epirubicin alone, was not able to show any advantage in terms of OS and time to progression. It must be highlighted that in both studies, as well as in the present study, LND was discontinued at the end of chemotherapy, whereas in our previous study in the metastatic setting,21 it was continued until progression. A plausible explanation for the lack of LND efficacy may be that the multidrug resistance (MDR) status was not previously assessed and that the untreated early BC patients were not all unequivocally resistant to anthracyclines, as expected in advanced stage of the disease. Therefore, the attractive hypothesis of MDR modulation cannot be supported or countered by the present study. Furthermore, the inhibitory effect of LND on neoplastic metabolism could be remarkable only in the presence of an elevated tumor burden, such as in the metastatic setting. Assuming that LND can be active until resistant clonal cells are selected (acquired resistance), we were not able to test either LND efficacy or failure by traditional assays. As a consequence, subclinical responses were not measurable. In addition, despite some promising results, data obtained in the treatment of solid tumors with modulators have been quite disappointing to date. This may be explained by the fact that the MDR phenotype alone does not completely account for the resistance of human cancer. Other resistance-related proteins (eg, glutathione S-transferase, metallothionein, O6-alkylguanine-DNA-alkyltransferase) can also be expressed in resistant tumors.27 Cell proliferation, vascularization, and apoptosis are involved in resistance as well. The deeper knowledge of multifactorial resistance and the synthesis of drugs capable of counteracting such mechanisms will allow us to design new drug combination strategies. Treatment resistance mechanisms are usually multiple, and therapeutic advantage must come from combined-modality treatments aimed at multiple targets. On the basis of a dose-response relationship, several trials have demonstrated the importance of an adequate dose of epirubicin in the metastatic and adjuvant setting. In women with metastatic BC, 120 mg/m2 administered as intravenous bolus every 3 weeks represents the reference dose for the use of epirubicin as a single agent.28 In the adjuvant setting, the same data are consistent with the hypothesis that escalating the dose greater than 90 mg/m2 might lead to improved outcome.29–31 We know that epirubicin is more lipophilic and capable of penetrating cells than ADM,32 and in the presence of a high dose of epirubicin, this effect could be more efficient than the ability of LND to modify the permeability of cell membranes. However, this observation can only be considered as an authors’ hypothesis. At the end of the 1980s, when this trial was started, one of the main points to be ascertained was to evaluate whether the increase of chemotherapy dose-intensity would be sufficient to improve the therapeutic efficacy. The only option was to prospectively analyze dose and timing of the regimen administered with or without recombinant hematopoietic growth factor support. Nowadays, neutropenia still remains one of the major dose-limiting toxicities of chemotherapeutic drugs and the main cause of dose reduction and delay of cancer treatment; neutropenia also might be a limiting factor of the therapeutic benefit. It has been long documented that the risk of infection increases as the severity of neutropenia increases. This prospective randomized study documented a significant decrease in neutropenia among patients in G-CSF arms, but hematologic toxicity was not significantly dose-limiting and, as a consequence, no differences were observed between G-CSF arms and control arms regarding dose-intensity, DFS, and OS. Our data suggest that a small reduction for any cause of an adequate dose of chemotherapy does not compromise survival of patients with early BC.
Finally, matching our results with those reported in the literature, it seems that the EC combination, at these doses and schedules, is as effective as other chemotherapy regimens containing more than two agents with respect to DFS and OS rates in the adjuvant setting (Table 6
The authors indicated no potential conflicts of interest.
Contributors are as follows: Federico Calabresi had the original idea for this study. Paola Papaldo, Massimo Lopez, and Paolo Marolla designed and coordinated the study. Gianluigi Ferretti and Serena Di Cosimo prepared the first draft of the report, to which Paola Papaldo subsequently contributed. Diana Giannarelli was responsible for the database and the statistical analysis and managed the data. All other authors took care of the patients enrolled in this study.
We thank the nurse staff of the Department of Medical Oncology for their technical support. We also thank the Italian women who took part in this study.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. DFS and OS curves were estimated using the Kaplan-Meier method. Data were expressed as 5-year survival rate with a 95% confidence interval (CI). Comparisons between the estimates were conducted across various treatment arms and treatment groups by the log-rank test. SPSS (SPSS, Inc, Chicago, IL) for Windows was used for statistical computation. 
