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ANTICANCER RESEARCH 24: 3257-3262 (2004)

Long-survival in Responding Patients with Metastatic Breast Treated with Doxorubicin- Combination. A Multicentre Phase II Trial

R. MATTIOLI1, P. LIPPE1, C. MASSACESI5, C. CAPPELLETTI1, D. NACCIARRITI2, R. BISONNI4, F. GRAZIANO3, E.T. MENICHETTI2, L. IMPERATORI1, E. TESTA3, G. LAICI1, A. BALLETTA6 and R.R. SILVA4

Medical Oncology Units: 1Fano, 2Senigallia, 3Urbino, 4Fabriano, 5Ancona, 6Cardiology Unit., Fano, Italy

Abstract. Background: The doxorubicin-docetaxel 18 and 33 months respectively, with ten long-survivors still combination is active in ; the aim of the present alive. Conclusion: This study confirmed the combination study was to evaluate the complete response rate and safety doxorubicin-docetaxel as a very active regimen for metastatic profile of the doxorubicin and docetaxel regimen as first-line breast cancer. Remarkably long survival times were observed in metastatic breast cancer patients. Patients not only in complete responders, but also in those patients who and Methods: Forty-three patients entered the study. Treatment responded partially. This might be equally attributed to first- plan was: doxorubicin (50 mg/m2, i.v. bolus) followed 1 hour line treatment and sequential maintenance hormonal therapy. later by docetaxel (75 mg/m2, i.v. infusion over 1 hour), q 3 weeks, for up to six courses. The patients achieving a response Both the (e.g., doxorubicin and ) or a stabilisation of disease after 6 courses were allowed to and the (e.g., and docetaxel) have been intensify the treatment with docetaxel (100 mg/m2, q 3 weeks) demonstrated to be among the most effective drugs against for up to 2 courses. G-CSF (or GM-CSF) was administered if metastatic breast cancer (MBC) (1). Doxorubicin-based clinically indicated. Results: Patients’ median age was 57 years regimens provided a superior response rate and improved (range 32-75) and 72% of them had visceral disease. A total of survival in MBC patients compared to non- 217 doxorubicin-docetaxel courses were delivered, with 70% of regimens (2), while taxanes have proven effectiveness in patients receiving all the 6 planned cycles. Among the 40 patients with anthracycline-resistant/refractory disease (3, patients assessable for response (WHO criteria), 7 (16%) 4). Moreover, the doxorubicin-paclitaxel combination achieved a complete remission and 22 (51%) a partial resulted in a higher response rate and time to progression remission, for an overall response rate (intent-to-treat) of 67% compared to single-agent doxorubicin or paclitaxel, but with (95% C.I.=53% to 81%). In 19 patients, the treatment was no difference in overall survival (5). The objective response intensified with two more single-agent docetaxel cycles, without in first-line chemotherapy was significantly better for ameliorating the response. Twenty-seven patients with doxorubicin (response rate [RR], 41%) than for paclitaxel oestrogen receptor-positive received hormonal therapy as (RR, 25%), with doxorubicin also achieving a longer median ‘maintenance’ after completing chemotherapy treatment. NCIC progression-free survival in a study published by Paridaens G3-G4 neutropenia was recorded in 58% of patients, with and collaborators (6). G/GM-CSF used in 23 (53%) patients and 91 (38%) cycles. On the other hand, docetaxel produced a significantly No patients experienced severe cardiac or neurological toxicity. higher RR than did doxorubicin (47.8% vs. 33.3%; p=0.008) No toxic death occurred. With a median follow-up of 41 in a randomised trial by Chan et al. (7). Moreover, data from months among alive patients, we observed in responder a Hoosier Oncology Group randomised trial in the neo- patients an overall median time to progression and survival of adjuvant setting suggest that sequential docetaxel after doxorubicin may result in a higher activity against breast cancer compared with the concomitant administration of the two drugs (8). Consequently, the doxorubicin-docetaxel Correspondence to: Paolo Lippe, M.D., Medical Oncology Unit, S. Croce Hospital, 61032 Fano, Italy. Tel/Fax: +39-0721-882396, e- combination has been studied in numerous phase I and phase mail: [email protected] II studies and has been demonstrated to be safe and highly effective (9). Based on these data and the promising efficacy Key Words: Doxorubicin, docetaxel, metastatic breast cancer. of docetaxel in MBC, we designed a phase II study of six

0250-7005/2004 $2.00+.40 3257 ANTICANCER RESEARCH 24: 3257-3262 (2004) cycles of doxorubicin-docetaxel combination, followed by a Table I. Characteristics of patients. further 2 cycles of docetaxel, without the routine Characteristics Patients administration of G/GM-CSF. The principal study endpoints were to evaluate the activity of the regimen, in particular the No. % rate of complete responses, and to assess the safety profile of the regimen with particular regard to myelotoxicity, Patients 43 cardiotoxicity and neurotoxicity. Secondary endpoints were Age (years) Median 57 the assessment of time to progression and overall survival. Range 32-75 ECOG performance status Patients and Methods 03274 11023 Patient selection. Forty-three eligible patients were enrolled into 213 the study at four Italian Medical Oncology Units: Fano, Estrogen receptor status Senigallia, Urbino and Fabriano. Eligibility criteria included: Positive/unknown 37 86 cyto-histologically proven MBC with bi-dimensionally measurable Negative 6 14 lesions, no previous chemotherapy for advanced disease, adjuvant Visceral disease 31 72 chemotherapy (without anthracyclines and/or taxanes) concluded Not visceral disease 12 28 Sites of metastases at least six months before diagnosis of MBC, no bone or brain Lung 17 40 metastases as the only measurable sites of disease, age ≥ 18 years Bone 12 28 and ≤ 80 years, ECOG performance status ≤2, normal organ Liver 12 28 9 function (leukocyte count ≥ 3.0 x 10 /L, neutrophil count ≥ 1.5 x Lymph nodes 9 21 9 9 10 /L, platelet count ≥ 100 x 10 /L, haemoglobin level ≥ 10 g/L, Pleura 6 14 serum creatinine level ≤0.15 mmol/L, hepatic levels no Skin and soft tissue 6 14 more than three times control or six times control in case of liver Breast 3 7 metastases), normal left ventricular ejection fraction (LVEF), no Brain 2 5 history of congestive (CHF), no atherosclerotic heart disease or irradiation of the mediastinum, not pregnant and using effective contraception if potentially childbearing, no prior malignancies except for radically cured basal cutaneous carcinoma and carcinoma in situ of the uterine cervix, and written informed consent. if total bilirubin and/or AST increased by more than 1.5- and 5- Patients with brain metastases were admitted if they did not fold, respectively. require emergency treatment and radiotherapy was deferred to the After six cycles of combination chemotherapy, patients achieving end of chemotherapy. In instances of occurrence of brain a response or a stabilisation of the disease were admitted to metastases-related symptoms during chemotherapy treatment, the intensify treatment with docetaxel (100 mg/m2, q 3 weeks) for up patient was immediately offered steroids, anti-epileptics and to 2 courses, according to the investigators’ decision. radiotherapy and the tumour response was evaluated only if at least Patients with positive hormonal receptors were allowed to 3 cycles were performed. receive hormonal therapy after completing chemotherapy treatment. Treatment plan. Doxorubicin, 50 mg/m2 i.v. bolus, followed, 1 hour later, by docetaxel, 75 mg/m2 i.v. as 1 hour infusion, were given on Evaluation of response and toxicity. Staging procedures at study entry day 1 and recycled on day 22. , 8 mg i.m., was included physical examination, electrocardiogram, LVEF assessment administered twice daily for 3 days, beginning 1 day before every by echocardiography, abdomen ultrasound and chest X-ray or chest- chemotherapy cycle in order to prevent fluid retention and abdomen CT scan, bone scan and skeletal radiograms (in case of hypersensitivity reaction. Filgrastim (G-CSF) or molgramostim abnormal bone scan), whilst brain CT scan was performed only if (GM-CSF) were administered if clinically indicated (febrile clinically indicated. All measurable sites of disease were assessed neutropenia, neutrophil count <500/mL, or with previous grade 3- within 4 weeks before chemotherapy and re-evaluated after cycles 3, 4 neutropenia) until the post-nadir neutrophil count was at least 6, 8 and then every 6 months during follow-up (WHO criteria). 10 x 109/L. Administration of both drugs was delayed or reduced Response duration was measured from the time of the first evidence in case of toxicity according to the protocol dosage adjustment of complete or partial remission until the time of progression. Time criteria: in event of a neutrophil count < 1.5 x 109/L and/or platelet to progression and overall survival were calculated as time from count < 100 x 109/L, administration of both drugs were delayed for study entry to progression of disease and to death, respectively. 1 week; a delay of more than 2 weeks resulted in removal from the All adverse events were assessed according to the National protocol. The doses of both drugs were reduced by 25% in the Cancer Institute of Canada common toxicity criteria (NCIC) (10). subsequent cycles if febrile neutropenia, grade 4 thrombocytopenia Echocardiography was repeated after cycle 6 and then every six and/or grade 3-4 nonhematological toxicities occurred. Finally, the months during follow-up, except for patients with prior left breast doses of both drugs were reduced by 50% if total bilirubin irradiation who repeated this examination even after cycle 3. In increased by 1.3- to 1.5- and/or AST by 2.5 to 5-fold above the case of LVEF decrease by more than 10%, or below the lower upper normal limits, whilst the patient was removed from the study normal value, the patient was referred to the cardiologist who

3258 Mattioli et al: Long Survival with Doxorubicin-Docetaxel in MBC

Figure 1. Time to progression (TTP) and overall survival (OS) in responders.

Table II. Patients’ toxicity.

Toxicity Patients with toxicity

Grades 1-2 Grade 3 Grade 4

No % No % No %

Haematology Granulocytopenia 7 16 12 28 13 30 Infection 0 0 2 5 1 2 Febrile neutropenia 0 0 1 2 0 0 Anemia 16 37 0 0 0 0 Thrombocytopenia 0 0 0 0 0 0

Gastrointestinal Nausea 15 35 8 19 0 0 Vomiting 10 23 5 11 0 0 3 7 0 0 0 0 Diarrhea 3 7 0 0 0 0

Neurologic Neurosensory 4 9 0 0 0 0 Neuromotor 4 9 0 0 0 0

Cardiac 4 9 0 0 0 0

Other Edema 0 0 0 0 0 0 Allergic reactions 0 0 0 0 0 0 Fatigue 14 32 4 9 0 0 Eye irritation 4 9 0 0 0 0

3259 ANTICANCER RESEARCH 24: 3257-3262 (2004) repeated the echocardiography to confirm the LVEF reduction. After progression, 10 (23%) patients received a second- In these patients echocardiography was subsequently performed line, and 13 (30%) patients a third-line or further-line every 3 months in order to find possible signs of CHF. In case of chemotherapy. To date 39 (91%) patients have progressed LVEF reduction > 20% or development of signs or symptoms of and 28 (65%) have died of disease. The median follow-up CHF, the patient was removed from the protocol and was period for the 15 patients still alive, as of March 2004, is 41 immediately referred to the Cardiology Unit. The use of was not allowed. months. For patients who responded to the treatment, the median time to progression was 18 months (range, 5–60) Statistical analysis. Given the high activity of the doxorubicin- and the median overall survival was 33 months (range, 9–67) docetaxel combination reported in MBC in previous experiences, (Figure 1). Long-survivors have been observed both among this study was specifically designed to assess the rate of complete complete (44+, 44+, 61+, 67+ months) and partial (31+, remissions in MBC patients treated with a combination of 34+, 35+, 43+, 44, 49+, 53+ months) responders. Among doxorubicin and docetaxel followed by consolidating docetaxel. non-responders, time to progression and overall survival was This schedule would be considered as promising if at least one complete remission occurred in the first 21 patients enrolled. A 8 and 15 months, respectively. total of 41 patients would be included in case of a positive result after the first step of the study. Treatment would be considered Toxicity. Overall, the treatment was well-tolerated (Table II). effective if at least 4 complete responses were recorded, with a NCIC neutropenia was: G3 in 28% of patients and 21 (9%) complete response probability ≥ 10% and a power of 90% (false- cycles, and G4 in 30% of patients and 8 (3%) cycles. G/GM- positive or ·-error < 5% and false-negative or ‚-error < 10%). CSFs were used in 23 patients (53%) and 91 cycles (38%). No Response duration, time to progression and overall survival were assessed by means of the Kaplan-Meier product-limit method (11). patients experienced severe thrombocytopenia and anemia. Non-hematological toxicity was mild. Regarding cardiac Results toxicity, a total of 28 patients had at least 2 measurements of the LVEF performed by echocardiography. Of these patients, Characteristics of patients and treatment. Forty-three 4 had sub-clinical cardiac toxicity (a reduction of LVEF > consecutive patients with proven MBC entered the study. 10% but less than 20%); none of the patients experienced There were 2 protocol violations: 1 patient with previous cardiac toxicity higher than grade 1 or congestive heart failure. and 1 patient with metastatic bone No major neurologic adverse event was recorded. As parameters, only. The characteristics of patients are listed expected, complete alopecia occurred in all patients. in Table I. Fifteen (35%) of them had prior adjuvant chemotherapy and visceral disease was present in 31 Discussion patients (72%). A total of 217 doxorubicin plus docetaxel courses were This multicentre phase II study confirmed the activity of the administered and 30 patients (70%) received all the 6 doxorubicin-docetaxel regimen with an overall response rate planned cycles. Treatment was intensified by two more of 67% and a rate of complete responses of 16%. docetaxel courses in 19 patients (44%): in 4 complete Intensification of treatment with 2 additional docetaxel as responders, 11 partial responders and 4 with stable disease. single-agent courses did not ameliorate the obtained Twenty-seven (63%) patients, with positive hormonal response. receptors, received hormonal agents, as maintenance The regimen showed an excellent toxicity profile, except therapy, at the end of the chemotherapy program: aromatase for haematological toxicity that was severe but not life- inhibitors and tamoxifen in 20 and 7 patients, respectively. threatening with the use of growth factor. Indeed, weekly administration of docetaxel has been reported to minimize Responses and survival. Among the 41 eligible patients, all haematological toxicity (12), therefore a weekly schedule of completed at least 3 cycles of chemotherapy and were docetaxel and doxorubicin may be better tolerated (13). assessable for response. A complete remission was In stage IV ‘oligometastatic’ breast cancer, defined as a documented in 7 patients (16%; 95% C.I., 5% to 27%) and low burden disease amenable to effective local control, the a partial response in 22 patients (51%; 95% C.I., 36% to availability of effective chemotherapy treatments may 66%), for an overall response rate, according to the intent- contribute to maintain the remission. Actually, a percentage to-treat principle, of 67% (95% C.I., 53% to 81%). The ranging from 1% to 3% of such patients treated with median duration of response was 16 months (range 3-60). A conventional treatments will maintain the complete stabilization of disease was recorded in 6 (14%) patients remission for prolonged periods of time, with some even and 6 (14%) patients progressed to treatment. None of the beyond 20 years (14). The importance of obtaining a 19 patients who received the intensified treatment with two complete response to prolong survival in metastatic breast more cycles of single-agent docetaxel had the response cancer has been widely stressed as well in those patients not (obtained after 6 combined cycles) ameliorated. candidate for local treatments because of diffuse disease

3260 Mattioli et al: Long Survival with Doxorubicin-Docetaxel in MBC

(15-18). In our series of non-oligometastatic breast cancer 8 Miller KD, McCaskill-Stevens W, Sisk J et al: Combination patients, with a highly active regimen we observed a relevant Versus sequential doxorubicin and docetaxel as primary proportion of responding patients (35%), both complete or chemotherapy for breast cancer: A randomized pilot trial of the Hoosier Oncology Group. J Clin Oncol 17: 3033-3037, 1999. partial responders, surviving beyond 36 months and who are 9 Sparano JA, O'Neill A, Schaefer PL et al: Phase II trial of still alive. Indeed, this may also be the result of the doxorubicin and docetaxel plus granulocyte colony-stimulating sequential ‘maintenance’ hormonal therapy that oestrogen- factor in metastatic breast cancer: Eastern Cooperative positive patients received after doxorubicin-docetaxel Oncology Group Study E1196. J Clin Oncol 18: 2369-77, 2000. therapy. Kloke et al. (19) found that maintenance hormone 10 National Cancer Institute of Canada Common Toxicity Criteria therapy with medroxyprogesterone acetate prolonged the (NCIC CTC), version 2.0, March 23rd 1998. http://ctep.info.nih.gov/ time to progression in patients with advanced breast cancer 11 Kaplan EL and Meyer P: Nonparametric estimation from incomplete observations. J Am Stat Ass 53: 457-81, 1958. after chemotherapy. Nowadays, with a wide range of new 12 Stemmler HJ, Gutschow K, Sommer H et al: Weekly docetaxel and active compounds, either cytotoxic or hormonal, the (Taxotere®) in patients with metastatic breast cancer. Ann sequential use of these agents may consistently prolong Oncol 12: 1393-1398, 2001. survival times. 13 Sancho JF, Enrech S, Menéndez P et al: Weekly docetaxel in In conclusion, this study confirmed the activity and safety combination with doxorubicin for advanced breast cancer. Ann of the doxorubicin-docetaxel combination in metastatic Oncol 11(S4): 29, 2000 (abstract). breast cancer, and the possibility of having long-survivors, 14 Hortobagyi GN: Can we cure limited metastatic breast cancer? J Clin Oncol 20: 620-623, 2002. not only among complete responders, but also among 15 Nieto Y, Nawaz S, Jones RB et al: Prognostic model for relapse patients who partially responded and sequentially submitted after high-dose chemotherapy with autologous stem-cell to a maintenance therapy. transplantation for stage IV oligometastatic breast cancer. J Clin Oncol 20: 707-718, 2002. References 16 Nieto Y, Cagnoni PJ, Shpall EJ et al: Phase II trial of high-dose chemotherapy with autologous stem cell transplant for stage IV 1 Honig SF: Treatment of metastatic disease: Hormonal and breast cancer with minimal metastatic disease. Clin Cancer Res chemotherapy. In: Harris JR, Lippman ME, Morrow M et al: 5: 1731-1737, 1999. (eds): Diseases of the Breast. Lippincott-Raven, Philadelphia, 17 Blumenschein GR, Buzdar AU, Tashima CK et al: Adjuvant PA, 1996, pp 669-734. chemoimmunotherapy of stage IV (NED) breast cancer. In: 2 A’Hern RPA, Smith IE and Ebbs SR: Chemotherapy and Salmon SE, Jones SE (eds): of Cancer. survival in advanced breast cancer: The inclusion of doxorubicin Amsterdam, The Netherlands, Elsevier North-Holland in Cooper type regimens. Br J Cancer 67: 801-805, 1993. Publishing Co, 1977, pp 147-152. 3 Bissery MC, Nohynek G, Sandernink GJ et al: Docetaxel: A 18 Buzdar AU, Blumenschein GR, Smith TL et al: Adjuvant review of preclinical and clinical experience-Part I. Clinical chemoimmunotherapy following regional therapy for isolated experience. Anti-Cancer Drugs 6: 1943-1951, 1995. recurrences of breast cancer (stage IV NED). J Surg Oncol 12: 4 Rowinsky EK and Donehower RC: Drug therapy: Paclitaxel. N 27-40, 1979. Eng J Med 332: 1004-1014, 1995. 19 Kloke O, Klaassen U, Oberhoff C et al: Maintenance treatment 5 Sledge GW, Neuberg D, Bernardo P et al: Phase III trial of with medroxyprogesterone acetate in patients with advanced doxorubicin, paclitaxel, and the combination of doxorubicin and breast cancer responding to chemotherapy: results of a paclitaxel as front-line chemotherapy for metastatic breast cancer: randomized trial. Essen Breast Cancer Study Group. Breast an intergroup trial (E1193). J Clin Oncol 21: 588-592, 2003. Cancer Res Treat 55: 51-59, 1999. 6 Paridaens R, Biganzoli L, Bruning P et al: Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: A European Organization for Research and Treatment of Cancer Randomized Study with cross-over. J Clin Oncol 18: 724, 2000. 7 Chan S, Friedrichs K, Noel D et al: Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic Received April 2, 2004 breast cancer. J Clin Oncol 17: 2341, 1999. Accepted July 13, 2004

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