Combinations of New and Old Agents for Breast Cancer Treatment: Future Directions

Publication
Article
OncologyONCOLOGY Vol 10 No 6
Volume 10
Issue 6

Several new agents undergoing clinical development appear to be effective and tolerable in the management of metastatic breast cancer. In recent years, a number of new and exciting combinations have been described, with an efficacy similar or, in some cases, apparently superior to that of standard chemotherapeutic regimens, such as FAC and CMF. The next several years will witness a large number of comparative clinical trials, the major purpose of which will be to establish the role of these new drugs and combinations in the management of metastatic breast cancer. Almost simultaneously, similar strategies will be pursued for adjuvant therapy for primary breast cancer, with the goal of improving the curative efficacy of current regimens. These prospects are exciting; however, enthusiasm must be tempered with the knowledge that long-term toxicity is always a distinct possibility. Therefore, the development of new combinations, especially in the setting of adjuvant chemotherapy, should follow a systematic, conservative strategy. [ONCOLOGY 10(Suppl):30-36, 1996]

ABSTRACT: Several new agents undergoing clinical development appear to be effective and tolerable in the management of metastatic breast cancer. In recent years, a number of new and exciting combinations have been described, with an efficacy similar or, in some cases, apparently superior to that of standard chemotherapeutic regimens, such as FAC and CMF. The next several years will witness a large number of comparative clinical trials, the major purpose of which will be to establish the role of these new drugs and combinations in the management of metastatic breast cancer. Almost simultaneously, similar strategies will be pursued for adjuvant therapy for primary breast cancer, with the goal of improving the curative efficacy of current regimens. These prospects are exciting; however, enthusiasm must be tempered with the knowledge that long-term toxicity is always a distinct possibility. Therefore, the development of new combinations, especially in the setting of adjuvant chemotherapy, should follow a systematic, conservative strategy. [ONCOLOGY 10(Suppl):30-36, 1996]

Introduction

For 15 years after the registration of doxorubicin in most westernindustrialized countries, developmental chemotherapy for breastcancer has consisted of the reutilization of multiple existingcytotoxic agents in different combinations and dose schedules[1]. The leading combinations (fluorouracil [5-FU], Adriamycin,and cyclophosphamide [FAC]; and cyclophosphamide, methotrexate,and 5-FU [CMF]) and the less commonly used alternatives (cyclophosphamide,Novantrone, 5-FU [CNF]; Novantrone, 5-FU, calcium leucovorin [NFL];and mitoxantrone, methotrexate, mitomycin [MMM]) remained themost effective and most commonly used for the management of metastaticbreast cancer [1-6]. However, overall response rates, completeremission rates, remission duration, and duration of survivalfor previously untreated patients with metastatic breast cancerand for previously treated patients with metastatic breast cancerremained unchanged. The introduction of dose intensification hasyet to prove its ability to affect survival [7-9].

Therefore, it was gratifying to see a number of new and effectivecytotoxic agents introduced into clinical trials over the past5 to 10 years. Phase II and limited phase III studies have demonstratedthe marked antitumor efficacy of the anthrapyrazoles [10-12],edatrexate [13-15], topotecan [16] and irinotecan [17,18], gemcitabine(Gemzar) [19], the taxanes [20-24], and vinorelbine (Navelbine)[25-30]. The challenge now is to incorporate these agents intothe optimal management of primary and metastatic breast cancer.This task is difficult under the best of circumstances; however,the potential number of combinations that could be developed withthese new agents and "older" agents is daunting.

Basic Principles of Combination Chemotherapy

There are some basic principles on which the development of combinationchemotherapy is based

  • The individual agents considered for the combination musthave independent antitumor activity against the tumor being treated.
  • There is minimal or no overlapping toxicity.
  • There is no known antagonistic interaction among two or moreof the agents being considered for the combination.

For any specific new drug, the challenge is to determine the bestway to integrate it into the management of a particular tumortype. Table 1 shows commonly used approaches to achieve such integration.The potential number of combinations and permutations is great,and each requires a large number of patients and a substantialinvestment of time and resources to test clinically. With theavailability of many new and active drugs, the number of permutationsincreases exponentially, and the difficulties in establishinga role for each agent in the standard management of breast carcinomaare multiplied many-fold.

Combinations Under Evaluation

Anthrapyrazoles, Camptothecin Analogs, Edatrexate, and Gemcitabine--Table2 offers combinations under evaluation for the anthrapyrazoles,camptothecin analogs, edatrexate, and gemcitabine [31-34] Informationabout these combinations is limited and follow-up short, but itis apparent that several of them have substantial antitumor activity,comparing favorably with that of previously existing standardcombination chemotherapy. Other combinations of these agents arein phase I trials; however, either no patients with breast cancerwere included or the intent was clearly to develop these combinationsfor evaluation in other tumors. Any combination that includesthese drugs and other active drugs against breast cancer wouldbe of interest to evaluate in breast carcinoma in humans. No combinationtrial reports were found for teloxantrone or piroxantrone. Basedon the available data, it is impossible to assess whether thesecombinations are of equal or higher efficacy than that of standardcombination chemotherapy for metastatic breast cancer (FAC orCMF).

Paclitaxel- and Docetaxel-Based Combinations--Table 3 similarlydescribes several paclitaxel (Taxol)- and docetaxel (Taxotere)-basedcombinations [35-48]. These agents have been under evaluationinternationally for 4 years; thus, there is more information availableabout their single-agent activity and about the activity of eachdrug in combination with several old and new agents [35-48]. Manymore combinations based on paclitaxel are currently in clinicaltrials, and other docetaxel-based combinations are under evaluation,but no preliminary reports are yet available. The combinationsincluded in Table 3 represent those that appear to be the mostactive, based on available published data. However, this informationis also limited in terms of comparative efficacy and, more important,comparative therapeutic index with older, existing combinations.

It is clear that taxane-based combinations appear to be at leastas effective as FAC or CMF, with the possibility that some ofthe newer combinations (taxane and doxorubicin or taxane and cisplatin[Platinol]) might be more effective than older, standard regimens.However, the increased toxicity observed with some of the newer,promising combinations dictates that formal, comparative evaluationis necessary and that strategies to reduce the frequency and severityof toxic effects must be explored and instituted.

Vinorelbine-Based Combinations--Table 4 describes combinationsbased on vinorelbine[49-62]. Of all the new drugs, vinorelbinewas introduced into clinical trials first, making the clinicalexperience with this new agent the richest. Combination therapywith vinorelbine has included all the major and most effectiveolder drugs and some of the newer agents described elsewhere inthis issue. Vinorelbine combinations also appear to be as effectiveas standard combinations. Although there is no evidence that theefficacy of vinorelbine combinations is greater than that of FACor CMF, the toxicity profile of these regimens appears to be excellent,and vinorelbine-based combinations might, as a matter of fact,be better tolerated than standard regimens.

Based on the data described in Tables 2-4, there is no obviousdifference in efficacy among combinations that include old andnew agents or among combinations of new agents only. What is apparentis that a large number of new, effective combinations are beingdeveloped. Establishing the role of each combination in breastcancer management is the next challenge.

Incorporating New Agents Into MetastaticBreast Cancer Therapy

New Drug Added to "Old" Agent--Most new combinationscontain an effective "old" drug and a new drug. Examplesof this strategy include vinorelbine + 5-FU, vinorelbine + doxorubicin,vinorelbine + mitoxantrone, paclitaxel + doxorubicin, paclitaxel+ cisplatin, paclitaxel + cyclophosphamide, docetaxel + doxorubicin,and gemcitabine + doxorubicin. The intent of these types of combinationsis to improve the efficacy of existing combinations by substitutinga new drug for an old one. Thus, the doublet paclitaxel + doxorubicinis an attempt to improve on doxorubicin + cyclophosphamide ordoxorubicin + 5-fluorouracil combinations. These two-drug combinationshave certainly been successful.

Entirely New Combinations--A different option is to developentirely new combinations. Examples of this strategy include paclitaxel+ vinorelbine, docetaxel + vinorelbine, edatrexate + paclitaxel,and losoxantrone + paclitaxel. A potential application of theuse of all new agents in combination is the development of treatmentstrategies whereby the new combination is used in addition toexisting, older combinations. With this strategy, fixed crossovercombinations or alternative schedules of administration of newand old regimens could be developed. An example of this approachis offered in Table 5. The hypothesis behind such strategies isthat the new combinations represent non-cross-resistant regimens,which will be cytotoxic to tumor cells resistant to the firstcombination being used.

Other Chemotherapeutic Regimens--The strategy of alternatingchemotherapeutic regimens has been used against metastatic breastcancer for the past 3 decades [63,64]. Unfortunately, there isno evidence from published trials that this strategy is more effectivethan the continuous use of a single combination. Fixed crossoverregimens have also been tried. Their efficacy against metastaticbreast cancer appears to be similar to that of single combinationregimens. However, there is some evidence that in the adjuvantsetting, their efficacy might be superior to that of a singleadjuvant chemotherapeutic combination [65,66]. Therefore, thereis substantial reason to develop these combinations and evaluatetheir relative efficacy.

Regimens with higher efficacy, even when accompanied by increasedtoxicity, might be used optimally as short induction regimens.For instance, this would be an appropriate option to induce ahigh percentage of complete remissions before high-dose chemotherapyand autologous stem cell rescue. In this manner, the maximum benefitof a relatively toxic combination with limited toxicity wouldbe obtained.

Choosing Agents for Clinical Testing

Combinations--With a staggering number of potential newcombinations, how should particular combinations be chosen foradditional clinical testing? One approach suggests that only themost successful combinations should proceed to phase III trials.However, on what criteria would this success be based? Responserates are notoriously unreliable and vary substantially from centerto center and group to group, depending on patient characteristics.Survival of breast cancer is seldom modified by a single treatmentregimen, and it might be unrealistic to expect major survivalmodifications from most new combinations. Similar problems applyto remission duration and time to progression, outcome measuresheavily influenced by patient characteristics and response data.However, combinations that reproducibly yield higher-than-average(more than 75%) overall remission rates, higher-than-average (morethan 30%) complete remission rates, and longer-than-expected (lessthan 12 months) remission durations deserve additional evaluationand systematic comparison with FAC or similarly effective standardregimens.

Another approach would be to base the selection process on proposedmechanisms of action and mechanisms of resistance of the agentsincluded in the "new" combination. In this model, combinationsconsisting of new members of "old" cytotoxic families(ie, a new alkylating agent or a new anthracycline) would havea lower priority for clinical development than drugs with novelmechanisms of action (eg, taxanes or topoisomerase I inhibitors).This strategy assumes that drugs with new mechanisms of cytotoxicitywould be more effective additions to the armamentarium than newanalogs of existing, effective drugs. Unfortunately, there isno strong evidence to support this assumption.

Fixed crossover designs would also be appropriate to test. Althoughalternating schedules of administration are conceptually attractive,it is unlikely that they will have a substantial impact on thenatural history of metastatic breast cancer until combinationswith complete remission rates in excess of 50% are developed.

Single Agents--Combination chemotherapy is certainly notthe only approach available to integrate new drugs into overallmanagement strategies. Cytotoxic agents with substantial antitumoractivity (vinorelbine, taxanes, and anthrapyrazoles) might bebest used as single agents, administered at their maximally tolerateddose. For agents with a steep dose-response curve, this approachmight be preferable to combination therapy, to avoid compromisingthe dose administered.

Some drugs are notoriously difficult to combine with other agents:witness the problems combining paclitaxel and docetaxel with doxorubicin,cisplatin, or even cyclophosphamide. In these instances, maximal-dosesingle-agent therapy might be as effective, and less toxic, thancombinations based on the same drug. This approach cannot profitfrom drug synergy, nor is it likely to be as effective as combinationtherapy in preventing the emergence of drug-resistant cell clones.However, it is a strategy that must be evaluated through clinicaltrials, as should all other approaches to drug integration.

Need for International Coordination--Regardless of theapproach undertaken, some mechanism of international coordinationwould be highly desirable to avoid duplication of effort and tostandardize, as much as possible, the methodology for evaluatingthe therapeutic index of novel combinations. Such coordinationcould begin with an international registry of clinical trials,in which all trials, regardless of sponsor, would be registered.This should be feasible and easily accessible to investigatorsworldwide on the Internet and through state-of-the-art electronictechnology. At the same time, agreement on a few basic standardsto enhance the quality of clinical research studies could makethe development of these new combinations substantially more efficient.

New Drug Combinations for Adjuvant Therapy

Despite the absence of sufficient comparative data on new combinationsversus standard chemotherapeutic regimens, several new drugs,or combinations that contain new drugs, have been introduced intoadjuvant and/or neoadjuvant chemotherapeutic settings. This mightbe slightly premature because of the concern related to the long-termeffects of any new drug introduced into clinical oncology. However,the limited efficacy of current adjuvant chemotherapeutic programsand the promising efficacy of the new drugs and new combinationsmake this approach quite tempting.

Table 6 describes several existing adjuvant chemotherapeutic programsthat include new agents or new combinations [1,36,71-75]. At thistime, only reports of tolerance and toxicity are available frommost of these studies. However, a few clinical trials, in whichnew drug-containing combinations were used in the preoperative(or neoadjuvant) setting, reported high response rates, includinghistologically documented complete remissions in some patients[73-75]. To date, adjuvant therapeutic programs based on new drugsappear to be well tolerated, and no serious or irreversible toxicityhas been observed. Adjuvant chemotherapy is administered to patientswith potentially curable disease. Therefore, only long-term observationwill define the risk-benefit ratio of these new agents and combinationsin the management of primary breast cancer.

Our knowledge and experience, based on standard chemotherapeuticregimens, suggest that secondary acute leukemias appear duringthe first 7 to 10 years after the administration of alkylatingagent therapy [76,77]. Acute leukemias appear earlier when theyare related to the administration of topoisomerase II inhibitors[78,79]. However, the development of secondary solid tumors isfurther delayed. Cumulative incidence curves suggest that even15 years after the administration of standard chemotherapy, thereis a continued increase in the development of second primary tumors[80,81]. Therefore, the introduction of a potentially carcinogenicnew drug into adjuvant therapy today will not be expected to produceits full effect until the year 2010 or beyond.

References:

1. Henderson IC: Chemotherapy for metastatic disease. In: HarrisJR, Hellman S, Henderson IC, et al (eds). Breast Diseases, 2nded, pp 604-665. Philadelphia, JB Lippincott, 1989.

2. Canellos GP, Pocock SJ, Taylor SG, et al: Combination chemotherapyfor metastatic breast cancer: Prospective comparison of multipledrug therapy with L-phenylalanine mustard. Cancer 38:1882-1886,1976.

3. Blumenschein GR, Cardenas JO, Freireich EJ, et al: FAC combinationchemotherapy for metastatic breast cancer. Proc Am Assoc CancerRes 15:193, 1974. Abstract.

4. Holmes FA, Yap HY, Esparza L, et al: Mitoxantrone, cyclophosphamide,and fluorouracil in metastatic breast cancer unresponsive to hormonaltherapy. Cancer 59:1992-1999, 1987.

5. Hainsworth JD, Andrews MB, Johnson DH, et al: Mitoxantrone,fluorouracil, and high-dose leucovorin: An effective, well-toleratedregimen for metastatic breast cancer. J Clin Oncol 9:1731-1736,1991.

6. Smith IE, Powles TJ: MMM (mitomycin/mitoxantrone/methotrexate):An effective new regimen in the treatment of metastatic breastcancer. Oncology 50:9-15, 1993.

7. Henderson IC, Hayes DF, Gelman R: Dose-response in the treatmentof breast cancer: A critical review. J Clin Oncol 6:1501-1515,1988.

8. Hortobagyi GN: The importance of dose-response in cytotoxictherapy for breast cancer. In: Henderson IC, Borden EC (eds).Advances in Breast Cancer Treatment, pp 47-62. London, Mediscript,1990.

9. Hortobagyi GN: Are the results of high-dose chemotherapy inbreast cancer really better than standard treatment? Bone MarrowTransplant 15:S260-S264, 1995.

10. Talbot DC, Smith IE, Mansi JL, et al: Anthrapyrazole CI 941:A highly active new agent in the treatment of advanced breastcancer. J Clin Oncol 9:2141-2147, 1991.

11. ten Bokkel Huinink W, Moore M, Smith I, et al: A phase IIstudy of losoxantrone (DuP 941) in advanced breast cancer. EurJ Cancer 29A:S78, 1993. Abstract.

12. Goldhirsch A, Morgan R, Yau J, et al: A phase II study ofDuP 937 in advanced breast cancer. Proc Am Soc Clin Oncol 11:76,1992. Abstract.

13. Schornagel JH, Van der Vegt S, Verweij J, et al: Phase IIstudy of edatrexate in chemotherapy-naive patients with metastaticbreast cancer. Ann Oncol 3:549-552, 1992.

14. Booser DJ, Dye CA, Clements SB, et al: Edatrexate (10-EDAM)for metastatic breast cancer: Phase II study. Proc Am Soc ClinOncol 13:109, 1994. Abstract.

15. Vandenberg T, Pritchard KI, Eisenhauer E, et al: Phase IIstudy of weekly 10-EDAM (edatrexate) as first line chemotherapyfor metastatic breast cancer: A National Cancer Institute of CanadaClinical Trials Group Study. Proc Am Soc Clin Oncol 11:51, 1992.Abstract.

16. Chang AY, Garrow G, Boros L, et al: Clinical and laboratorystudies of topotecan in breast cancer. Proc Am Soc Clin Oncol14:105, 1995. Abstract.

17. Bonneterre J, Pion JM, Adenis A, et al: A phase II study ofa new camptothecin analogue CPT-11 in previously treated advancedbreast cancer patients. Proc Am Soc Clin Oncol 12:94, 1993. Abstract.

18. Taguchi T: A novel anti-tumor agent, CPT-11 (a topoisomeraseI inhibitor). Ann Oncol 5(suppl 8):179, 1994. Abstract.

19. Carmichael J, Possinger K, Philip P, et al: Difluorodeoxycytidine(gemcitabine): A phase II study in patients with advanced breastcancer. Proc Am Soc Clin Oncol 12:64, 1993. Abstract.

20. Reichman BS, Seidman AD, Crown JPA, et al: Paclitaxel andrecombinant human granulocyte colony-stimulating factor as initialchemotherapy for metastatic breast cancer. J Clin Oncol 11:1943-1951,1983.

21. Holmes FA, Walters RS, Theriault RL, et al: Phase II trialof Taxol, an active drug in the treatment of metastatic breastcancer. J Natl Cancer Inst 83:1797-1805, 1991.

22. Fumoleau P, Chevallier B, Kerbrat P, et al: First line chemotherapywith Taxotere in advanced breast cancer: A phase II study of theEORTC clinical screening group. Proc Am Soc Clin Oncol 12:56,1993. Abstract.

23. Trudeau ME, Eisenhauer E, Lofters W, et al: Phase II studyof Taxotere as first line chemotherapy for metastatic breast cancer:A National Cancer Institute of Canada Clinical Trials Group Study.Proc Am Soc Clin Oncol 12:64, 1993. Abstract.

24. Seidman AD, Hudis CA, Crown JPA, et al: Phase II evaluationof Taxotere (RP56976, NSC 628503) as initial chemotherapy formetastatic breast cancer. Proc Am Soc Clin Oncol 12:63, 1993.Abstract.

25. Fumoleau P, Delgado FM, Delozier T, et al: Phase II trialof weekly intravenous vinorelbine in first-line advanced breastcancer chemotherapy. J Clin Oncol 11:1245-1252, 1993.

26. Garcia-Conde J, Lluch A, Martin M, et al: Phase II trial ofweekly IV Navelbine in first line advanced breast cancer chemotherapy.Ann Oncol 5:854-857, 1994.

27. Canobbio L, Boccardo F, Pastorino G, et al: Phase II studyof Navelbine in advanced breast cancer. Semin Oncol 16(2)(suppl4):33-36, 1989.

28. Weber B, Vogel C, Jones S, et al: A U.S. multicenter phaseII trial of Navelbine in advanced breast cancer. Proc Am Soc ClinOncol 12:61, 1993. Abstract.

29. Romero A, Rabinovich M, Vallejo C, et al: Promising preliminaryresults of weekly Navelbine as first line chemotherapy for metastaticbreast cancer. Proc Am Soc Clin Oncol 12:76, 1993. Abstract.

30. Bruno S, Lira-Puerto V, Texeira L, et al: Phase II trial withNavelbine in the treatment of advanced breast cancer patients.Ann Oncol 3(suppl 1):126, 1992. Abstract.

31. Cobb P, Burris H, Peacock N, et al: Phase I trial of losoxantroneplus paclitaxel given every 21 days. Proc Am Soc Clin Oncol 14:476,1995. Abstract.

32. Tolcher AW, O'Shaughnessy JA, Weiss RB, et al: A phase I studyof topotecan (a topoisomerase I inhibitor) in combination withdoxorubicin (a topoisomerase II inhibitor). Proc Am Soc Clin Oncol13:157, 1994. Abstract.

33. Fennelly D, Gilewski T, Hudis CA, et al: Phase I trial ofsequential edatrexate followed by paclitaxel: A design based onin vitro synergy in patients with advanced breast cancer. ProcAm Soc Clin Oncol 14:101, 1995. Abstract.

34. Perez-Manga G, Lluch A, Garcia-Conde J, et al: Early phaseII study of gemcitabine in combination with doxorubicin in advancedbreast cancer. Proc Am Soc Clin Oncol 14:97, 1995. Abstract.

35. Holmes FA, Newman RA, Madden T, et al: Schedule dependentpharmacokinetics in a phase I trial of Taxol and doxorubicin asinitial chemotherapy for metastatic breast cancer. Ann Oncol 5:197,1994. Abstract.

36. Holmes FA: Update: The M. D. Anderson Cancer Center experiencewith paclitaxel in the management of breast carcinoma. Semin Oncol22:9-15, 1995.

37. Fisherman JS, McCabe M, Noone M, et al: Phase I study of Taxol,doxorubicin, plus granulocyte-colony stimulating factor in patientswith metastatic breast cancer. J Natl Cancer Inst 15:189-194,1993.

38. Gianni L, Straneo M, Capri G, et al: Optimal dose and sequencefinding study of paclitaxel by 3h infusion combined with bolusdoxorubicin in untreated metastatic breast cancer patients. ProcAm Soc Clin Oncol 13:74, 1994. Abstract.

39. Gehl J, Ejlersen M, Boesgaard M, et al: Efficacy and toxicityof combined doxorubicin and paclitaxel in metastatic breast cancer(preliminary results). Ann Oncol 5:39, 1995. Abstract.

40. Gelmon KA: Biweekly paclitaxel (Taxol) and cisplatin in breastand ovarian cancer. Semin Oncol 21:24-28, 1994.

41. Tolcher AW, Gelmon KA: Interim results of a phase I/II studyof biweekly paclitaxel and cisplatin in patients with metastaticbreast cancer. Semin Oncol 22:28-32, 1995.

42. Wasserheit C, Alter R, Speyer J, et al: Phase II trial ofpaclitaxel and cisplatin in women with metastatic breast cancer.Proc Am Soc Clin Oncol 13:100, 1994. Abstract.

43. Tolcher A, Cowan K, Riley J, et al: Phase I study of paclitaxeland cyclophosphamide and G-CSF in metastatic breast cancer. ProcAm Soc Clin Oncol 13:73, 1994. Abstract.

44. Hainsworth JD, Jones SE, Erland JB: Paclitaxel, mitoxantrone,5-fluorouracil, and high dose leucovorin in the treatment of metastaticbreast cancer. Proc Am Soc Clin Oncol 14:91, 1995. Abstract.

45. Ibrahim N, Hortobagyi GN, Valero V, et al: Phase I study ofvinorelbine (Navelbine) and paclitaxel by simultaneous 3-hourinfusion for untreated metastatic breast cancer. Proc Am AssocCancer Res 36:242, 1995. Abstract.

46. Verweij J, Planting AST, van der Burg MEL, et al: A phaseI study of docetaxel (Taxotere) and cisplatin in patients withsolid tumors. Ann Oncol 5:180, 1994. Abstract.

47. Dieras V, Gruia G, Pouillart P, et al: A phase I study ofthe combination of docetaxel and doxorubicin in first line CTtreatment of metastatic breast cancer: Preliminary results. BreastCancer Res Treat 37:91, 1996. Abstract.

48. Fumoleau P, Delacroix V, Perrocheau G, et al: Docetaxel incombination with vinorelbine as first line CT in patients withMBC: Preliminary results on 22 entered patients. Breast CancerRes Treat . In press. Abstract.

49. Hortobagyi GN: Future directions for vinorelbine. Semin Oncol22:80-87, 1995.

50. Spielmann M, Dorval T, Turpin F, et al: Phase II trial ofvinorelbine/doxorubicin as first-line therapy of advanced breastcancer. J Clin Oncol 12:1764-1770, 1994.

51. Chadjaa M, Izzo J, May-Levin F: Preliminary data on 4'epiadriamycine-vinorelbine:A new combination in advanced breast cancer. Proc Am Soc ClinOncol 12:88, 1993. Abstract.

52. Dieras V, Pierga J, Extra J, et al: Results of a combinationof Navelbine and fluorouracil in advanced breast cancer with agroup sequential design. Ann Oncol 3(suppl 5):46, 1992. Abstract.

53. Ferrero JM, Wendling JL, Hoch M: Mitoxantrone-vinorelbineas first line chemotherapy in metastatic breast cancer: A pilotstudy. Proceedings of the IVth International Congress on AnticancerChemotherapy 222, 1993. Abstract.

54. Wendling JL, Nouyrigat P, Vallicioni D: Cisplatinum-mitoxantrone-vinorelbineas first line chemotherapy for metastatic breast cancer: A pilotstudy. Proc Am Soc Clin Oncol 14:142, 1995. Abstract.

55. Meriggi F, Zaniboni A, Arcangeli G, et al: VELF: An activeoutpatient regimen for aggressive metastatic breast cancer: Preliminaryresults. Proc Am Soc Clin Oncol 13:91, 1994. Abstract.

56. Spielmann M, Brain E, Sari C, et al: Salvage chemotherapywith combination of mitoxantrone and vinorelbine in resistantto anthracyclines advanced breast cancer. Proceedings of the IVthInternational Congress on Anticancer Chemotherapy 61, 1993. Abstract.

57. Santos R, Rufino C, Batageltj E, et al: Navelbine and mitomycinin anthracyclines resistant or refractory advanced breast cancer:Preliminary report. Eur J Cancer 29A:S78, 1993. Abstract.

58. Gralla RJ, Kardinal CG, Clark RA, et al: Enhancing the safety,efficacy, and dose intensity of vinorelbine (Navelbine) in combinationchemotherapy regimens. Proc Am Soc Clin Oncol 12:336, 1993. Abstract.

59. Colleoni M, Gaion F, Sgarbossa G, et al: Phase II study ofmitoxantrone, fluorouracil plus folates and vinorelbine in patientswith previously treated advanced breast cancer. Proceedings ofthe Vth International Congress on Anticancer Chemotherapy 1:112,1995. Abstract.

60. Fabi A, Tonachella R, Savarese A, et al: A phase II trialof vinorelbine and Thiotepa in metastatic breast cancer. Ann Oncol6:187-189, 1995.

61. Iaffaioli RV, Tortoriello A, Facchini G, et al: Chemotherapywith combination of carboplatin (CBDCA) and vinorelbine (VRB)in advanced breast cancer. Eur J Cancer 29A:S87, 1993. Abstract.

62. Nistico C, Pace A, Ranuzzi M, et al: Systemic and neurologicaltoxicity of combined treatment epirubicin and vinorelbine in advancedbreast cancer: Preliminary results. Proc Am Soc Cancer Res 36:367,1995. Abstract.

63. Blumenschein GR, Hortobagyi GN, Richman SP, et al: Alternatingnoncross-resistant combination chemotherapy and active nonspecificimmunotherapy with BCG or MER BCG for advanced breast carcinoma.Cancer 45:742-749, 1980.

64. Theriault RL, Hortobagyi GN, Kau SW, et al: Sequential multiagentchemotherapy incorporating cisplatin, doxorubicin, and cyclophosphamidein the treatment of metastatic breast cancer. Cancer 62:2105-2110,1988.

65. Bonadonna G, Zambetti M, Valagussa P: Sequential or alternatingdoxorubicin and CMF regimens in breast cancer with more than threepositive nodes: Ten year results. JAMA 273:542-547, 1995.

66. Perloff M, Norton L, Korzun A, et al: Advantage of an Adriamycincombination plus Halotestin after initial cyclophosphamide, methotrexate,5-fluorouracil, vincristine and prednisone (CMFVP) for adjuvanttherapy of node-positive stage II breast cancer. Proc Am Soc ClinOncol 5:70, 1986. Abstract.

67. Demetri GD, Berry D, Younger J, et al: Dose-intensified cyclophosphamide/doxorubicinfollowed by Taxol as adjuvant systemic chemotherapy for node-positivebreast cancer (CALGB 9141): Randomized comparison of two doselevels of G-CSF. Proc Am Soc Clin Oncol 13:65, 1994. Abstract.

68. Hudis CA, Seidman AD, Baselga J, et al: Sequential high doseadjuvant doxorubicin, paclitaxel, and cyclophosphamide with G-CSFis feasible for women with resected breast cancer and (4(+) lymphnodes. Proc Am Soc Clin Oncol 13:65, 1994. Abstract.

69. Hortobagyi GN: Management of breast cancer: Status and futuretrends. Semin Oncol 22:101-107, 1995.

70. O'Shaughnessy JA, Cowan KH: Current status of paclitaxel inthe treatment of breast cancer. Breast Cancer Res Treat 33:27-37,1995.

71. Seidman AD, Hudis CA, Norton L: Memorial Sloan-Kettering CancerCenter experience with paclitaxel in the treatment of breast cancer:from advanced disease to adjuvant therapy. Semin Oncol 22(4)(suppl8):3-8, 1995.

72. French Northern Oncology Group: Mitoxantrone and vinorelbineas a primary treatment of locoregional breast cancer. Proceedingsof the IVth International Congress on Anticancer Chemotherapy223, 1993. Abstract.

73. van Praagh I, Pivoteau N, Cure H, et al: Tolerance and efficiencyof a regimen of vinorelbine-epirubicin-methotrexate in first lineneoadjuvant and metastatic breast cancer. Ann Oncol 3(suppl 5):99,1992. Abstract.

74. Chollet P, Charrier S, Brain E, et al: Neoadjuvant chemotherapyin breast cancer: High pathological response rate induced by intensiveanthracycline-based regimen. Proc Am Soc Clin Oncol 14:130, 1995.Abstract.

75. van Praagh I, Leduc B, Feillel V, et al: Neoadjuvant VEM chemotherapyregimen for operable breast cancer: Results of a cooperative studyon 69 patients. Proc Am Soc Clin Oncol 14:136, 1995. Abstract.

76. Detourmignies L, Castaigne S, Stoppa AM, et al: Therapy-relatedacute promyelocytic leukemia: A report on 16 cases. J Clin Oncol10:1430-1435, 1992.

77. Curtis RE, Boice JD, Stovall M, et al: Risk of leukemia afterchemotherapy and radiation treatment for breast cancer. N EnglJ Med 326:1745-1751, 1992.

78. Murphy SB: Secondary acute myeloid leukemia following treatmentwith epipodophyllotoxins. J Clin Oncol 11:199-201, 1993.

79. Winick NJ, McKenna RW, Shuster JJ, et al: Secondary acutemyeloid leukemia in children with acute lymphoblastic leukemiatreated with etoposide. J Clin Oncol 11:209-217, 1993.

80. Herring MK, Buzdar AU, Smith TL, et al: Second neoplasms afteradjuvant chemotherapy for operable breast cancer. J Clin Oncol9:269-275, 1986.

81. Valagussa P, Tancini G, Bonadonna G: Second malignancies afterCMF for resectable breast cancer. J Clin Oncol 5:1138-1142, 1987.

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